Next Article in Journal
Physiological Associations between Vitamin B Deficiency and Diabetic Kidney Disease
Previous Article in Journal
Bioresorbable Magnesium-Based Stent: Real-World Clinical Experience and Feasibility of Follow-Up by Coronary Computed Tomography: A New Window to Look at New Scaffolds
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 11
Issue 4
10.3390/biomedicines11041152
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

TP53 Alterations in Myelodysplastic Syndromes and Acute Myeloid Leukemia

by
Ramy Rahmé
1,2,3,4,
Thorsten Braun
4,
James J. Manfredi
1,5 and
Pierre Fenaux
6,*
1
Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2
Institut de Recherche Saint Louis (IRSL), INSERM U1131, Université Paris Cité, 75010 Paris, France
3
Ecole Doctorale Hématologie–Oncogenèse–Biothérapies, Université Paris Cité, 75010 Paris, France
4
Clinical Hematology Department, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Sorbonne Paris Nord, 93000 Bobigny, France
5
The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
6
Senior Hematology Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Cité, 75010 Paris, France
*
Author to whom correspondence should be addressed.
Biomedicines 2023, 11(4), 1152; https://doi.org/10.3390/biomedicines11041152
Submission received: 16 March 2023 / Revised: 30 March 2023 / Accepted: 6 April 2023 / Published: 11 April 2023
(This article belongs to the Special Issue p53 Signaling in Cancer Progression and Therapy)
Browse Figures
Review Reports Versions Notes

Abstract

:
TP53 mutations are less frequent in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) than in solid tumors, except in secondary and therapy-related MDS/AMLs, and in cases with complex monosomal karyotype. As in solid tumors, missense mutations predominate, with the same hotspot mutated codons (particularly codons 175, 248, 273). As TP53-mutated MDS/AMLs are generally associated with complex chromosomal abnormalities, it is not always clear when TP53 mutations occur in the pathophysiological process. It is also uncertain in these MDS/AML cases, which often have inactivation of both TP53 alleles, if the missense mutation is only deleterious through the absence of a functional p53 protein, or through a potential dominant-negative effect, or finally a gain-of-function effect of mutant p53, as demonstrated in some solid tumors. Understanding when TP53 mutations occur in the disease course and how they are deleterious would help to design new treatments for those patients who generally show poor response to all therapeutic approaches.

1. Introduction

The transcription factor p53, encoded by the TP53 gene in humans, is one of the most studied tumor suppressor proteins. In normal cells, p53 activity is low, but in response to DNA damage and numerous other stress signals, p53 levels rise dramatically and result in the activation and transcription of genes with important roles in cell cycle arrest, senescence, apoptosis, metabolism, and differentiation [1]. The sum of these activities is to ensure that an abnormal cell fails to arise and proliferate. During normal hematopoiesis, p53 activities preserve genome integrity and regulate several cellular processes that maintain the normal stem cell pool and serve as a barrier to tumorigenesis [2,3].
Perturbations in p53 activity or p53-dependent pathways are required for the development of most cancers [4], and there is evidence in many situations to suggest that the restoration or reactivation of physiological p53 function may be therapeutic [5,6,7,8]. Various mechanisms are responsible for the disruption of p53 activity in cancer, mainly deletion or mutation of the TP53 gene, and overexpression of the p53 negative regulators Mdm2 and Mdm4 [9,10,11]. Several isoforms are encoded by the TP53 gene and appear to play different roles in tumorigenesis/cancer progression [12] or response to treatment, for example in acute myeloid leukemia (AML) [13]. Regardless of the mechanism behind p53 dysfunction, the downstream consequences are profound due to the very large spectrum of biological activities in which p53 is normally implicated. The clinical correlation between p53 mutational status in cancer cells and resistance to treatment has been studied since the 1990s. In breast cancer, presence of a TP53 mutation is associated with resistance to doxorubicin [14,15]. Similarly, ovarian cancer patients harboring a TP53 mutation are less sensitive to treatment with cisplatin [16,17]. Moreover, the association of TP53 mutation with chemoresistance and poor prognosis has also been observed in lung [18], gastric, and colorectal cancers [19], as well as in hematological malignancies [20,21]. Apart from triggering chemoresistance, p53 mutants are also able to attenuate cancer response to radiotherapy [14,19,22].
Myelodysplastic syndromes (MDS) are a clonal hematopoietic stem cell disorders characterized by cell dysplasia, ineffective hematopoiesis that leads to cytopenias (mainly anemia) and a variable risk of progression to AML [23]. Furthermore, AML is characterized by clonal expansion of undifferentiated myeloid precursors, resulting in impaired hematopoiesis and life-threatening cytopenias. Among the prognostic factors identified in both malignancies, presence of a mutation in the TP53 gene indicates a particularly dismal prognosis irrespective of the treatment administered [24]. In this review, we present an overview of the current knowledge about mutant p53 activities in MDS/AML, and discuss treatment strategies that may potentially enter clinical testing.

2. Characteristics of TP53 Mutations in MDS/AML

TP53 gene mutations are reported in about 50% of solid tumors, but only 5–10% of de novo myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, while these mutations are rare in MDS/AML with a normal karyotype (1%), they are seen in 40–50% of secondary and therapy-related cases [20,25,26,27], and in 80% of complex monosomal karyotypes (CK) that include 17p and/or 5q deletion [28,29]. Other inactivating mechanisms of wild-type p53 function include overexpression of MDM2 and MDM4, negative regulators of p53, in 20–30% and 40–50% of AML cases, respectively [30,31,32,33,34]. Unfortunately, treatment with Mdm2 inhibitors has not so far demonstrated a substantial effect in these cases [35]. Inactivation of p14-ARF, a positive regulator of p53, has been more rarely reported in AML [32,36,37].
As in solid tumors, most TP53 mutations in MDS/AML cluster in exons 4 to 8 that encode the DNA binding domain [38,39]. Nearly 75% of the mutants are missense: recurrent hotspot variants are also observed, as in solid tumors, and at the same frequent codons such as the contact mutants at codons 248 and 273, and the structural mutants at codons 175 and 245 [40]. The number of cooperating driver mutations is usually very low in TP53-mutated MDS/AML, and even absent in 85% of the cases [41].
TP53 alteration in MDS/AML can be monoallelic or biallelic [42]. Monoallelic mutations, with point mutation of only one TP53 allele, represent 25 to 30% of the cases. They are particularly seen in MDS with isolated 5q deletion [43,44,45,46], but can also be discovered in various MDS and AML with non-complex karyotype by systematic NGS analysis, generally at low variant allelic frequency (VAF) [42]. In 70 to 75% of the cases, TP53 alterations are biallelic, generally resulting from point mutation on one TP53 allele (usually missense) and loss of the other allele, through 17p deletion or monosomy 17. The great majority of MDS/AMLs with biallelic alteration have indeed complex monosomal karyotype resulting in 17p deletion, very often with 5q deletion [47]. On the other hand, monoallelic TP53 mutations can lead to genomic instability, chromosomal loss and chromothripsis (also known as “chromosome shattering” that leads to large structural rearrangements in chromosomes [48]) including loss of heterozygosity (LOH) through 17p deletion [49], and therefore resulting in a biallelic hit. TP53 mutations, especially in the biallelic state, are associated with resistance to most treatments, including chemotherapy, hypomethylating agents, and even allogeneic stem cell transplantation, as the risk of relapse post-transplant is very high, at least in case of biallelic alterations [50,51,52,53]. Monoallelic mutations are also, to a lesser extent, associated with a certain resistance to treatment, for example to lenalidomide–an immuno-modulatory drug used in MDS with del(5q) [43,54], but have generally a more limited impact on survival.

3. When Do TP53 Mutations Arise in MDS and AML Cells?

Whether TP53 mutations occur early or late in the evolution of MDS and AML remains uncertain in most situations. In well-performed studies in therapy-related MDS/AML, it was found that cells harboring the leukemia-specific TP53 mutation preexisted to the first cancer and were positively selected by treatment for this cancer (chemotherapy or radiation) to which they were resistant [55,56]. Progressive evolution was seen through genomic instability and chromothripsis with inactivation of the second TP53 allele, as seen above [49] (Figure 1). TP53 mutations are also among the mutations found in healthy individuals with clonal hematopoiesis of indeterminate potential (CHIP), who have an increased risk of developing various blood cancers [57,58]. However, DNMT3A, TET2, and ASXL1 mutations largely predominate in CHIPs seen in patients with no prior history of treated cancer, and CHIPs with TP53 mutation are mainly seen in patients having received chemotherapy or radiotherapy for a prior cancer, where they increase the risk of therapy-related MDS/AML, potentially by the selection mechanism just described above [55,59,60,61,62,63,64].
It is still unclear in other MDS/AML situations when TP53 mutations arise. In MDS with isolated 5q deletion, detectable monoallelic TP53 mutations, often at very low VAF and sometimes multiple, are found in 20% of the patients at diagnosis [43,44,45,46]. Whether they occur during disease evolution or very early in minor undetectable clones (by conventional methods) that could undergo positive selection, including by treatment with lenalidomide, is unclear. In those MDS with isolated del(5q) and monoallelic TP53 mutation, as in the therapy-related model described above, progression to AML is generally preceded by acquisition of a complex karyotype, including del(17p) and biallelic TP53 inactivation [65,66] (Figure 2).
In myeloproliferative neoplasms, TP53 mutations are seen in about 20% of the cases with progression to MDS/AML. They appear to be late events, although once again small TP53 mutant clones, undetectable by conventional techniques, may have occurred earlier in the disease course [67,68,69,70,71,72,73]. When TP53-mutated clones appear during the disease course would be important to determine, as their early detection in myeloid malignancies could allow to target them pharmacologically, potentially preventing progression to full-blown biallelic TP53 MDS/AML.
TP53 mutations could represent early leukemogenic events in many situations, and they have been indeed reported in pre-leukemic hematopoietic stem cells (HSCs) of AML patients [74,75]. Major roles of TP53 are related to cell-cycle control, DNA repair and apoptosis. Dysregulation of these pivotal functions might be an alternative mechanism to epigenetic modifications in establishing a proleukemogenic state in HSCs [76]. By transforming HSCs into pre-leukemic stem cells (pre-LSCs), TP53 mutations substantially contribute to the development of AML and its resistance to conventional treatments [55,77,78]. Moreover, TP53-mutated pre-LSCs retain their ability to differentiate into mature blood cells both in patient-derived mouse xenografts and patients with AML [78]. Clonogenic assays revealed that patient-specific TP53 mutations are present in the vast majority of HSC-derived colonies (median, 97%; range, 45 to 100%), with only a paucity of cooperating mutations in known cancer genes, as seen above. Copy-number alterations, as already described, appear to be secondary events after the onset of a first TP53 mutation [79,80].

4. How Can p53 Mutants Drive Leukemia Development and Maintain the Leukemic State?

Mutant p53 proteins can potentially contribute to MDS/AML pathophysiology and progression through different molecular mechanisms: protein inactivation and loss of function in the case of biallelic hits; a dominant-negative effect of the mutant over germline wild-type p53; or finally a gain-of-function effect of the mutant protein. Those different mechanisms are not exclusive. In the last two situations, monoallelic mutations may already be pathogenic. The fact that poor prognosis in MDS/AMLs with TP53 mutation is mainly seen in patients with biallelic alterations [42]—where MDS/AML cells have no more functional p53–intuitively suggests that loss of wild-type p53 functions is the major oncogenic determinant, at least in late disease stages.
In tumors in general, the predominance of mutant p53 protein expression over the simple loss of p53, given that missense mutants overshadow nonsense/truncating mutants, suggests an inherent biological advantage for TP53 mutants in human cancers [81,82,83]. This is in contrast to many other tumor suppressor genes that undergo deletion through the course of tumor initiation or development, such as PTEN, BRCA1, and RB1 [84]. Thus, because p53 normally acts as a tetramer, p53 mutants may play a dominant-negative effect on the activity of any remaining wild type p53 in the cancer cell [85,86]. In addition, missense mutations could also result in the gain of novel functions that contribute to tumorigenesis [87,88,89,90].
Whereas many scientific works have demonstrated mutant p53 activities in solid tumors [91,92,93], only few studies have addressed these functions in AML. Boettcher et al. showed in engineered human cell lines that gain-of-function (GOF) activities might be dispensable in AML [94], and that the dominant-negative expression (DNE) of TP53 mutants appeared to be the main driver of leukemogenesis, leading to p53 inactivation. However, in that work, TP53 mutations were introduced in AML lines that already depended on the activity of fusion oncoproteins, a situation where GOF activities of the mutants may not be essential for the cells. They also reported that missense mutations did not worsen prognosis in AML patients treated with intensive chemotherapy compared to patients with truncating mutations, adding another argument against any GOF in AML. However, intensive chemotherapy may not be the best treatment option in TP53-mutated patients, and these findings may therefore not be sufficient to rule out some GOF activities of missense mutants in AML. Therefore, AML murine models with various TP53 mutations are developed, including by our group, in order to avoid potential biases associated with cell line-based studies (work in progress).
Furthermore, the Scott Lowe Lab developed an original RNA interference-based approach to generate murine AMLs by knocking down the expression of the two tumor suppressors Mll3 and Nf1, thus partly mimicking 7q and 17p deletions found in human AMLs, respectively (“MNP” model for Mll3, Nf1 and P53) [95]. This model was used to generate murine p53-mutated AML harboring the missense mutant R172H (equivalent to the human R175H hotspot mutant) [96]. In that setting, mutant p53 showed GOF activities through the pluripotency factor Foxh1 [96]. In line with those results, our in vivo studies also revealed GOF transcriptional activities for mutant p53 that conferred a proliferation advantage over p53 inactivation (manuscript in preparation). In a follow-up paper, Liu et al., using the MNP model on HSCs harboring the 11B3 chromosomal deletion–a 4 Mb region on mouse chromosome 11 that is syntenic to human 17p13.1 [97], showed that 11B3 deletion promoted the development of more aggressive AML compared to the p53-null background, suggesting that other genes than TP53 drive the selection for 17p loss during leukemogenesis [97].

5. Treatment of TP53 Mutated MDS/AML

5.1. The Current Disappointing Situation

All clinical studies have shown the poor outcome of TP53-mutated MDS/AML cases with current therapeutic approaches including intensive chemotherapy, hypomethylating agents (HMAs, i.e., azacitidine and decitabine), with or without other agents, and allogeneic stem cell transplantation, at least in the case of biallelic alterations that are generally associated with complex monosomal karyotypes–which constitutes the most frequent situation.
Both missense and truncating TP53 mutations confer resistance to treatment in AML patients. TP53 mutation appears to be, even in complex karyotypes, an independent poor prognostic factor [50,51]. In addition, in low-risk MDS with 5q deletion [43], monoallelic TP53 mutations are associated with lower rates of response to lenalidomide and a higher risk of progression to AML (generally associated with acquisition of a complex karyotype, and loss of the second TP53 allele) [98]. Hence, the management of TP53-mutated MDS/AMLs is still highly challenging [51,52,53].
Intensive chemotherapy yields very low complete remission rates in AML with (generally) biallelic TP53 hits (around 30%), and prolonged myelosuppression [66,99]. HMAs [51,53] and more recently combinations of HMA and Venetoclax [100], a highly selective bioavailable inhibitor of the anti-apoptotic BCL2 protein, have increased the response rate in MDS/AML with complex monosomal karyotypes and biallelic TP53 hits (up to 50–60%), but those responses are short and median survival remains at around one year. Finally, allogeneic stem cell transplantation is associated with a very high risk of relapse post-transplant in these patients [101,102], but its results are better in patients with monoallelic mutations, especially patients with isolated 5q deletion [103].

5.2. How Can Treatment of MDS/AMLs with TP53 Mutation Be Improved?

Many agents are being considered and tested to overcome the resistance of TP53-mutated cells to conventional treatments. A non-exhaustive list can be found in Table 1. They generally aim at inducing tumor cell death in the absence of a functional p53 protein or at reconforming mutant p53 protein to a functional state, although some may implicate the immune system such as CD47 blockers. Many of these agents have so far been only tested in vitro. In some cases, those drugs are used in other therapeutic indications–hence, they have already demonstrated a good toxicity profile–and could potentially be “repurposed” for the treatment of TP53-mutated MDS/AMLs. We will focus on a few of those drugs, stressing the fact that, so far, none of those agents has demonstrated a significant benefit in randomized phase III studies.

5.3. Drugs Currently Used in Clinical Trials

APR-246 (Eprenetapopt): A variety of molecules have been developed through which a native-like function of mutant p53 can be reactivated. Only one of those molecules, APR-246, has reached the clinical trial stage. APR-246 induces the refolding of mutant p53 in vitro and in mice, which enhances its DNA binding ability, resulting in the upregulation of wild-type p53 target genes and the induction of cell death by apoptosis [5,104]. Mechanistically, the decomposition products of APR-246, specifically the compound MQ (methylene quinuclidinone), covalently associate and form adducts with thiols of p53 mutants such as R175H, R248Q, and R273H [105]. Studies also uncovered a mutant p53-independent effect of APR-246: it depletes glutathione content and sensitizes mutant p53-containing cancer cells to oxidative stress [106,107]. This molecule was evaluated in ovarian carcinoma in combination with chemotherapy [108], and in combination with azacitidine for the treatment of TP53-mutated high-risk MDS and AML [109,110]. Two phase II trials of APR-246 plus azacitidine showed promising results [109,110], but the phase III trial against azacitidine monotherapy did not show a significant improvement in both complete remission and survival rates (p = 0.13).
Magrolimab: CD47 is a cell surface protein belonging to the immunoglobulin family, expressed by virtually all cells in the body [111]. The interaction of CD47 with SIRPα on the surface of phagocytic cells gives a “do not eat me” signal to the innate immune system: this system is used by cancer cells to evade detection and destruction by macrophages [112]. CD47 was found to be highly expressed on AML cells [113] and to be associated with adverse prognosis [114]. Magrolimab is a monoclonal antibody that targets CD47. A first-line treatment with the triple combination of azacitidine, venetoclax, and magrolimab gave promising results in patients with TP53-mutated AML: overall response rate at 74% and complete remission rate at 41% [115]. A phase III randomized trial comparing azacitidine/venetoclax/magrolimab to azacitidine/venetoclax is currently enrolling (ENHANCE-3, NCT05079230).

5.4. Drugs so Far Used Only in Preclinical Models

MCL1 inhibition: Myeloid Cell Leukemia 1 (MCL-1) protein is a member of the Bcl2 family of anti-apoptotic proteins (which also includes Bcl-2, Bcl-W and Bcl-xL). Through their BH3 domains, these proteins, in particular Mcl-1 and Bcl-xL, bind and sequester the pro-apoptotic proteins Bak and Bax on the mitochondrial outer membrane, thus preventing their activation [116]. In AML cell lines and patient-derived xenografts, Thijssen et al. found that TP53 deficiency altered the cell balance in BCL2 family members [117]. Upon exposure to the Bcl-2 inhibitor venetoclax, the absence of apoptosis after engagement of mitochondrial outer membrane permeabilization (MOMP) led to a state termed “Minority MOMP” that is deleterious and paradoxically promotes DNA damage and genomic instability [118,119]. This state further enhances the fitness of TP53-deficient cells, their competition ability and resistance to drugs. Combined treatment of venetoclax with an MCL1 inhibitor successfully induced apoptosis that improved the survival of mice engrafted with three different TP53-deficient xenografts [117].
Arsenic trioxide: A recent work showed that arsenic trioxide (ATO), a drug used in the treatment of acute promyelocytic leukemia, can rescue the conformation of multiple structural p53 mutants [120]. Mechanistically, ATO interacts with the four sulfur-containing p53 residues (Cys124, Cys135, Cys141, and Met133) that define the arsenic-binding pocket (ABP). Covalent interactions of ATO with the coordinating cysteines result in a pronounced reorganization of the ABP. Most mutants were stabilized by ATO in this study, but only some were transcriptionally rescued. In addition, ATO was effective in one patient-derived xenograft of non-small cell lung carcinoma expressing the R282W mutant, as well as in two cell line-derived xenografts expressing the R175H mutant including CEM-C1, a human T acute lymphoblastic leukemia cell line.
Niclosamide: Niclosamide is an oral salicylanilide derivative approved by the FDA since 1960 as a drug that acts against infections caused by parasitic worms or helminths (Anthelmintic drug) [121,122]. Characterized by a mild mitochondrial uncoupling activity, this drug has an excellent safety profile in humans as transient and mild mitochondrial uncoupling is tolerable in normal cells [123,124]. Several reports suggest that niclosamide has anticancer activities by impeding various growth promoting pathways such as mTOR, STAT3 and NF-kB [125,126,127,128,129,130]. More recently, niclosamide showed a noteworthy anticancer activity in p53-deficient and -mutant ovarian cancer cells. Surprisingly, wild type p53 cells were less vulnerable to niclosamide-induced mitochondrial uncoupling [131]. These findings, if confirmed in other mutant p53 models, could lead to the repositioning of niclosamide as an anticancer drug that specifically targets TP53-mutated tumors.
Synthetic lethality strategies: In the area of cancer biology, an oncogenic mutation or a tumor suppressor defect may offer cancer cells a survival advantage based on a secondary survival signal [132]. Accordingly, cancer cells become vulnerable if this secondary survival signal is targeted. Accumulating evidence revealed that TP53 gene mutations provide an opportunity for achieving synthetic lethality in cancer cells. Several studies support this notion by showing that inactivation of the G2 or S checkpoint-associated pathways (i.e., ATR/CHK1, ATM/CHK2, p38MAPK/MK2, WEE1) is synthetic lethal to p53-deficient cancer cells [133,134]. For instance, ATR inhibition induced synthetic lethality in TP53-deficient chronic lymphocytic leukemia cells [135]. Similarly, treatment with the ATR inhibitor AZ-20 increased sensitivity to etoposide in p53-null and R273 mutant cells, but had a lesser impact on p53 wild type cells [136]. Furthermore, recent phase 1 and 2 clinical trials demonstrated that AZD1775, a potent and selective WEE1 inhibitor, enhanced tumor response to carboplatin in TP53-mutated ovarian cancer patients who were refractory to first-line treatment [137,138]. Therefore, the vulnerability caused by TP53 mutations in cancer cells can be efficiently targeted as a strategy to treat patients.
Targeting mutant p53-derived neoantigens: p53 mutants are degraded by the proteasome: the resulting peptides are processed and presented by human leukocyte antigen (HLA) molecules on the cell surface as neoantigens that are recognized by T cell receptors (TCRs) [139,140]. HMTEVVRHC peptide (mutant amino acid underlined), derived from p53-R175H mutant, binds to the HLA allele A*02:01 that is present in more than 40% of U.S. Caucasians [139,141]. Very recently, Han-Chung Hsiue et al. described the development of a TCR-mimic antibody highly specific to the HLA A*02:01-restricted p53-R175H-derived neoantigen. A bispecific version can lyse R175H-mutated cancer cells in a fashion that is dependent on the presence of the neoantigen, both in vitro and in vivo [142]. This novel protein-based approach is very promising and could rapidly enter clinical development.
Table
Table 1. List of drugs targeting p53 mutants used in clinical trials.
Table 1. List of drugs targeting p53 mutants used in clinical trials.
DrugMechanism
of Action		TrialCancer TypeResultsReference
APR-246 Reconforming agentNCT04383938Advanced solid
tumor (bladder,
gastric, NSCLC,
urothelial)		Phase Ib
Combination with
Pembrolizumab		Park H
et al. [143]
NCT03072043MDS/AMLPhase II
Plus Azacitidine
Response rates:
MDS 73%
Oligoblastic AML 64%		Sallman D
et al. [109]
NCT03588078MDS/AMLPhase II
Plus Azacitidine
Response rates:
MDS 62%
AML 33%		Cluzeau T
et al. [110]
NCT03931291MDS/AMLPhase II
Plus Azacitidine
Maintenance therapy following transplant
1-year survival 78.8%		Mishra A
et al. [144]
NCT03745716MDS/AMLPhase III
Plus Azacitidine vs. Azacitidine
No significant difference for primary endpoint		Press release
NCT04214860MDS/AMLPhase I
Plus Azacitidine
& Venetoclax		Trial completed
Not reported
Arsenic
trioxide		Reconforming agentNCT03855371MDS/AMLPhase I
Plus Decitabine		Currently enrolling
Ganetespib
(STA-9090)		HSP90 inhibitor
Mutant p53 degradation		NCT02012192High-grade
platinum-resistant
ovarian cancer		Phase I/II
Combined with Paclitaxel
Safe use of the combination		Ray-Coquard
et al. [145]
AtorvastatinMutant p53 degradationNCT03560882MDS/AML
Solid tumors		Pilot trialCurrently enrolling
Vorinostat
(SAHA)		HDAC inhibitor
Mutant p53 degradation		NCT02042989Metastatic solid tumorsPhase I
Plus Ixazomib (proteasome inhibitor)
Median survival 7.3 months		Wang Y
et al. [146]
NCT01339871Metastatic solid tumorsPhase I
Plus Pazopanib (VEGF inhibitor)
Median survival 12.7 months		Wang Y
et al. [146]
Adavosertib
(AZD1775/
MK-1775)		Wee1 inhibitor
Synthetic lethality		NCT01164995Refractory ovarian cancerPhase II
Plus Carboplatin
Median survival 12.6 months		Leijen S
et al. [138]
NCT03668340Recurrent uterineserous carcinomaPhase II
Monotherapy
Median PFS 6.1 months
Median response 9.0 months		Liu
et al. [147]

6. Conclusions and Future Perspectives

As previously discussed, the most important lesson we learnt from repeated sequencing studies of human samples is that TP53 mutations are generally very early events in the leukemia development process (although this remains uncertain in lower risk MDS with isolated del 5q) (Figure 1 and Figure 2). From a biochemical perspective, two mechanisms can possibly explain the acquisition of a TP53 mutation in a somatic cell. (1) The induction of p53-mediated apoptosis in response to various stresses may lead to the selection of precancerous cells that harbor a TP53 mutation. In addition, cell competition between hematopoietic stem cells (HSCs), a phenomenon controlled by p53 [148,149], could also favor mutated cells [62]. (2) Alternatively, the TP53 gene locus could be associated with DNA fragile sites that are highly sensitive to genomic instability [150,151,152]. Genomic instability can be detected in precancerous lesions prior to the detection of mutations in tumor suppressor genes such as TP53 [153], and is likely to arise from carcinogen- or oncogene-induced replication stress during the formation of solid tumors. This replication stress triggers p53-dependent cell death at the early stage of cancer, but leads to the development of TP53 mutations that further accelerates genome instability and chromothripsis as the cancer progresses to a later stage [153]. For instance, the hotspot p53 mutants R248W and R273H were found to interact with the MRN (Mre11-Rad50-NBS1) complex and to prevent its association with the DNA double-strand breaks, consequently leading to amplified replication stress and impaired DNA damage response [154]. In this second scenario, p53 mutants would act as “supporters” rather than “sources” of genome instability in sporadic cancers.
In AML, mutant p53 probably initiates leukemic transformation in HSCs (i.e., acting as the source) and the dominant-negative effect may be important at this very early stage. This step is followed by chromosomal losses and “catastrophic” rearrangements [49]. When patients are diagnosed with overt disease, the mutant protein is highly expressed in leukemic cells whereas the wild type allele is always lost among many other tumor suppressors. However, it is still not clear today whether any mutant gain-of-function activities are indispensable for leukemia maintenance at this late stage.
Therefore, in order to gain better understanding on the roles a missense mutant p53 plays in leukemogenesis, one should analyze in detail the following steps: (1) the acquisition of the mutation in HSCs; (2) the interaction of mutant p53 with wild type p53 when both proteins are still present in the same HSC; (3) the genome instability steps that lead or accompany the leukemia process. For instance, in the case of nonsense mutants, it is unknown whether the sole deletion of the second allele is sufficient to drive leukemogenesis as there might be a need to delete other genes on 17p [97]; and finally (4) the pathways that maintain leukemia. From a clinical point of view, we prioritize the investigation of the last step as patients are seen at the stage of overt disease. Engineered cell lines may not offer the appropriate tools to investigate mutant p53 functions as this approach disregards the mutant p53-dependent multistep process that leads to leukemia. Animal model should be preferable in this setting as compound transgenic genotypes combined with conditional gene expression in the hematopoietic system can help dissect this multistep process.
Overall, the main difficulty to study mutant p53 functions in acute leukemias is inherent to the leukemia development process that is deemed to be stochastic in this specific setting. Different AML patients with the same TP53 missense mutation may not have biologically equivalent diseases. In addition, different mutants might have different oncogenic functions–if any–at a late stage. Our focus for drug discoveries should probably be on targeting mutant p53 degradation/depletion and on generic cellular processes that are important for the maintenance of aneuploidy in leukemic cells such as DNA replication and chromosome segregation.

Author Contributions

Conceptualization, R.R. and P.F.; writing—original draft preparation, R.R.; writing—review and editing, R.R., T.B., J.J.M. and P.F.; supervision, P.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Vousden, K.H.; Prives, C. Blinded by the Light: The Growing Complexity of p53. Cell 2009, 137, 413–431. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Pant, V.; Quintás-Cardama, A.; Lozano, G. The p53 pathway in hematopoiesis: Lessons from mouse models, implications for humans. Blood 2012, 120, 5118–5127. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Aloni-Grinstein, R.; Shetzer, Y.; Kaufman, T.; Rotter, V. p53: The barrier to cancer stem cell formation. FEBS Lett. 2014, 588, 2580–2589. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Kandoth, C.; McLellan, M.D.; Vandin, F.; Ye, K.; Niu, B.; Lu, C.; Xie, M.; Zhang, Q.; McMichael, J.F.; Wyczalkowski, M.A.; et al. Mutational landscape and significance across 12 major cancer types. Nature 2013, 502, 333–339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Bykov, V.J.N.; Issaeva, N.; Shilov, A.; Hultcrantz, M.; Pugacheva, E.; Chumakov, P.; Bergman, J.; Wiman, K.G.; Selivanova, G. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat. Med. 2002, 8, 282–288. [Google Scholar] [CrossRef]
  6. Junttila, M.R.; Karnezis, A.N.; Garcia, D.; Madriles, F.; Kortlever, R.M.; Rostker, F.; Brown Swigart, L.; Pham, D.M.; Seo, Y.; Evan, G.I.; et al. Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 2010, 468, 567–571. [Google Scholar] [CrossRef] [Green Version]
  7. Feldser, D.M.; Kostova, K.K.; Winslow, M.M.; Taylor, S.E.; Cashman, C.; Whittaker, C.A.; Sanchez-Rivera, F.J.; Resnick, R.; Bronson, R.; Hemann, M.T.; et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 2010, 468, 572–575. [Google Scholar] [CrossRef] [Green Version]
  8. Wang, Y.; Suh, Y.-A.; Fuller, M.Y.; Jackson, J.G.; Xiong, S.; Terzian, T.; Quintás-Cardama, A.; Bankson, J.A.; El-Naggar, A.K.; Lozano, G. Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation. J. Clin. Investig. 2011, 121, 893–904. [Google Scholar] [CrossRef]
  9. Vogelstein, B.; Lane, D.; Levine, A.J. Surfing the p53 network. Nature 2000, 408, 307–310. [Google Scholar] [CrossRef]
  10. Toledo, F.; Wahl, G.M. Regulating the p53 pathway: In vitro hypotheses, in vivo veritas. Nat. Rev. Cancer 2006, 6, 909–923. [Google Scholar] [CrossRef]
  11. Wasylishen, A.R.; Lozano, G. Attenuating the p53 Pathway in Human Cancers: Many Means to the Same End. Cold Spring Harb. Perspect. Med. 2016, 6, a026211. [Google Scholar] [CrossRef] [PubMed]
  12. Vieler, M.; Sanyal, S. p53 Isoforms and Their Implications in Cancer. Cancers 2018, 10, 288. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Ånensen, N.; Hjelle, S.M.; Van Belle, W.; Haaland, I.; Silden, E.; Bourdon, J.-C.; Hovland, R.; Taskén, K.; Knappskog, S.; Lønning, P.E.; et al. Correlation analysis of p53 protein isoforms with NPM1/FLT3 mutations and therapy response in acute myeloid leukemia. Oncogene 2012, 31, 1533–1545. [Google Scholar] [CrossRef] [Green Version]
  14. Bergh, J.; Norberg, T.; Sjögren, S.; Lindgren, A.; Holmberg, L. Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nat. Med. 1995, 1, 1029–1034. [Google Scholar] [CrossRef] [PubMed]
  15. Aas, T.; Børresen, A.L.; Geisler, S.; Smith-Sørensen, B.; Johnsen, H.; Varhaug, J.E.; Akslen, L.A.; Lønning, P.E. Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat. Med. 1996, 2, 811–814. [Google Scholar] [CrossRef] [PubMed]
  16. Shelling, A.N. Role of p53 in drug resistance in ovarian cancer. Lancet 1997, 349, 744–745. [Google Scholar] [CrossRef]
  17. Petty, R.; Evans, A.; Duncan, I.; Kurbacher, C.; Cree, I. Drug resistance in ovarian cancer—The role of p53. Pathol. Oncol. Res. 1998, 4, 97–102. [Google Scholar] [CrossRef]
  18. Horio, Y.; Takahashi, T.; Kuroishi, T.; Hibi, K.; Suyama, M.; Niimi, T.; Shimokata, K.; Yamakawa, K.; Nakamura, Y.; Ueda, R. Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res. 1993, 53, 1–4. [Google Scholar]
  19. Hamada, M.; Fujiwara, T.; Hizuta, A.; Gochi, A.; Naomoto, Y.; Takakura, N.; Takahashi, K.; Roth, J.A.; Tanaka, N.; Orita, K. The p53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers. J. Cancer Res. Clin. Oncol. 1996, 122, 360–365. [Google Scholar] [CrossRef]
  20. Wattel, E.; Preudhomme, C.; Hecquet, B.; Vanrumbeke, M.; Quesnel, B.; Dervite, I.; Morel, P.; Fenaux, P. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 1994, 84, 3148–3157. [Google Scholar] [CrossRef] [Green Version]
  21. Wilson, W.H.; Teruya-Feldstein, J.; Fest, T.; Harris, C.; Steinberg, S.M.; Jaffe, E.S.; Raffeld, M. Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin’s lymphomas. Blood 1997, 89, 601–609. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Koch, W.M.; Brennan, J.A.; Zahurak, M.; Goodman, S.N.; Westra, W.H.; Schwab, D.; Yoo, G.H.; Lee, D.J.; Forastiere, A.A.; Sidransky, D. p53 mutation and locoregional treatment failure in head and neck squamous cell carcinoma. J. Natl. Cancer Inst. 1996, 88, 1580–1586. [Google Scholar] [CrossRef] [PubMed]
  23. Fenaux, P.; Platzbecker, U.; Ades, L. How we manage adults with myelodysplastic syndrome. Br. J. Haematol. 2020, 189, 1016–1027. [Google Scholar] [CrossRef]
  24. Papaemmanuil, E.; Döhner, H.; Campbell, P.J. Genomic Classification in Acute Myeloid Leukemia. N. Engl. J. Med. 2016, 375, 900–901. [Google Scholar] [CrossRef]
  25. Slingerland, J.M.; Minden, M.D.; Benchimol, S. Mutation of the p53 gene in human acute myelogenous leukemia. Blood 1991, 77, 1500–1507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Fenaux, P.; Jonveaux, P.; Quiquandon, I.; Laï, J.L.; Pignon, J.M.; Loucheux-Lefebvre, M.H.; Bauters, F.; Berger, R.; Kerckaert, J.P. P53 gene mutations in acute myeloid leukemia with 17p monosomy. Blood 1991, 78, 1652–1657. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Fenaux, P.; Preudhomme, C.; Quiquandon, I.; Jonveaux, P.; Laï, J.L.; Vanrumbeke, M.; Loucheux-Lefebvre, M.H.; Bauters, F.; Berger, R.; Kerckaert, J.P. Mutations of the P53 gene in acute myeloid leukaemia. Br. J. Haematol. 1992, 80, 178–183. [Google Scholar] [CrossRef] [PubMed]
  28. Ok, C.Y.; Patel, K.P.; Garcia-Manero, G.; Routbort, M.J.; Peng, J.; Tang, G.; Goswami, M.; Young, K.H.; Singh, R.; Medeiros, L.J.; et al. TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. J. Hematol. Oncol. 2015, 8, 45. [Google Scholar] [CrossRef] [Green Version]
  29. Haase, D.; Stevenson, K.E.; Neuberg, D.; Maciejewski, J.P.; Nazha, A.; Sekeres, M.A.; Ebert, B.L.; Garcia-Manero, G.; Haferlach, C.; Haferlach, T.; et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia 2019, 3, 1747–1758. [Google Scholar] [CrossRef] [Green Version]
  30. Quintás-Cardama, A.; Hu, C.; Qutub, A.; Qiu, Y.H.; Zhang, X.; Post, S.M.; Zhang, N.; Coombes, K.; Kornblau, S.M. p53 pathway dysfunction is highly prevalent in acute myeloid leukemia independent of TP53 mutational status. Leukemia 2017, 31, 1296–1305. [Google Scholar] [CrossRef]
  31. Bueso-Ramos, C.E.; Yang, Y.; deLeon, E.; McCown, P.; Stass, S.A.; Albitar, M. The human MDM-2 oncogene is overexpressed in leukemias. Blood 1993, 82, 2617–2623. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Faderl, S.; Kantarjian, H.M.; Estey, E.; Manshouri, T.; Chan, C.Y.; Rahman Elsaied, A.; Kornblau, S.M.; Cortes, J.; Thomas, D.A.; Pierce, S.; et al. The prognostic significance of p16(INK4a)/p14(ARF) locus deletion and MDM-2 protein expression in adult acute myelogenous leukemia. Cancer 2000, 89, 1976–1982. [Google Scholar] [CrossRef] [PubMed]
  33. Dey, A.; Tergaonkar, V.; Lane, D.P. Double-edged swords as cancer therapeutics: Simultaneously targeting p53 and NF-kappaB pathways. Nat. Rev. Drug Discov. 2008, 7, 1031–1040. [Google Scholar] [CrossRef]
  34. Wade, M.; Li, Y.-C.; Wahl, G.M. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat. Rev. Cancer 2013, 13, 83–96. [Google Scholar] [CrossRef] [Green Version]
  35. Khurana, A.; Shafer, D.A. MDM2 antagonists as a novel treatment option for acute myeloid leukemia: Perspectives on the therapeutic potential of idasanutlin (RG7388). OncoTargets Ther. 2019, 12, 2903–2910. [Google Scholar] [CrossRef] [Green Version]
  36. Müller-Tidow, C.; Metzelder, S.K.; Buerger, H.; Packeisen, J.; Ganser, A.; Heil, G.; Kügler, K.; Adigüzel, G.; Schwäble, J.; Steffen, B.; et al. Expression of the p14ARF tumor suppressor predicts survival in acute myeloid leukemia. Leukemia 2004, 18, 720–726. [Google Scholar] [CrossRef] [PubMed]
  37. Chen, D.; Kon, N.; Zhong, J.; Zhang, P.; Yu, L.; Gu, W. Differential effects on ARF stability by normal versus oncogenic levels of c-Myc expression. Mol. Cell 2013, 51, 46–56. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Lai, J.L.; Preudhomme, C.; Zandecki, M.; Flactif, M.; Vanrumbeke, M.; Lepelley, P.; Wattel, E.; Fenaux, P. Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a high incidence of P53 mutations. Leukemia 1995, 9, 370–381. [Google Scholar]
  39. Soenen, V.; Preudhomme, C.; Roumier, C.; Daudignon, A.; Laï, J.L.; Fenaux, P. 17p Deletion in acute myeloid leukemia and myelodysplastic syndrome. Analysis of breakpoints and deleted segments by fluorescence in situ. Blood 1998, 91, 1008–1015. [Google Scholar] [CrossRef] [Green Version]
  40. Sabapathy, K.; Lane, D.P. Therapeutic targeting of p53: All mutants are equal, but some mutants are more equal than others. Nat. Rev. Clin. Oncol. 2018, 15, 13–30. [Google Scholar] [CrossRef]
  41. Prochazka, K.T.; Pregartner, G.; Rücker, F.G.; Heitzer, E.; Pabst, G.; Wölfler, A.; Zebisch, A.; Berghold, A.; Döhner, K.; Sill, H. Clinical implications of subclonal TP53 mutations in acute myeloid leukemia. Haematologica 2019, 104, 516–523. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Bernard, E.; Nannya, Y.; Hasserjian, R.P.; Devlin, S.M.; Tuechler, H.; Medina-Martinez, J.S.; Yoshizato, T.; Shiozawa, Y.; Saiki, R.; Malcovati, L.; et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat. Med. 2020, 26, 1549–1556. [Google Scholar] [CrossRef] [PubMed]
  43. Jädersten, M.; Saft, L.; Smith, A.; Kulasekararaj, A.; Pomplun, S.; Göhring, G.; Hedlund, A.; Hast, R.; Schlegelberger, B.; Porwit, A.; et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J. Clin. Oncol. 2011, 29, 1971–1979. [Google Scholar] [CrossRef]
  44. Sebaa, A.; Ades, L.; Baran-Marzack, F.; Mozziconacci, M.-J.; Penther, D.; Dobbelstein, S.; Stamatoullas, A.; Récher, C.; Prebet, T.; Moulessehoul, S.; et al. Incidence of 17p deletions and TP53 mutation in myelodysplastic syndrome and acute myeloid leukemia with 5q deletion. Genes Chromosomes Cancer 2012, 51, 1086–1092. [Google Scholar] [CrossRef] [PubMed]
  45. Scharenberg, C.; Giai, V.; Pellagatti, A.; Saft, L.; Dimitriou, M.; Jansson, M.; Jädersten, M.; Grandien, A.; Douagi, I.; Neuberg, D.S.; et al. Progression in patients with low- and intermediate-1-risk del(5q) myelodysplastic syndromes is predicted by a limited subset of mutations. Haematologica 2017, 102, 498–508. [Google Scholar] [CrossRef] [Green Version]
  46. Lodé, L.; Ménard, A.; Flet, L.; Richebourg, S.; Loirat, M.; Eveillard, M.; Le Bris, Y.; Godon, C.; Theisen, O.; Gagez, A.-L.; et al. Emergence and evolution of TP53 mutations are key features of disease progression in myelodysplastic patients with lower-risk del(5q) treated with lenalidomide. Haematologica 2018, 103, e143–e146. [Google Scholar] [CrossRef] [Green Version]
  47. Volkert, S.; Kohlmann, A.; Schnittger, S.; Kern, W.; Haferlach, T.; Haferlach, C. Association of the type of 5q loss with complex karyotype, clonal evolution, TP53 mutation status, and prognosis in acute myeloid leukemia and myelodysplastic syndrome. Genes Chromosomes Cancer 2014, 53, 402–410. [Google Scholar] [CrossRef]
  48. Forment, J.V.; Kaidi, A.; Jackson, S.P. Chromothripsis and cancer: Causes and consequences of chromosome shattering. Nat. Rev. Cancer 2012, 12, 663–670. [Google Scholar] [CrossRef]
  49. Rücker, F.G.; Dolnik, A.; Blätte, T.J.; Teleanu, V.; Ernst, A.; Thol, F.; Heuser, M.; Ganser, A.; Döhner, H.; Döhner, K.; et al. Chromothripsis is linked to TP53 alteration, cell cycle impairment, and dismal outcome in acute myeloid leukemia with complex karyotype. Haematologica 2018, 103, e17–e20. [Google Scholar] [CrossRef] [Green Version]
  50. Bejar, R.; Stevenson, K.E.; Caughey, B.; Lindsley, R.C.; Mar, B.G.; Stojanov, P.; Getz, G.; Steensma, D.P.; Ritz, J.; Soiffer, R.; et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J. Clin. Oncol. 2014, 32, 2691–2698. [Google Scholar] [CrossRef] [Green Version]
  51. Bally, C.; Adès, L.; Renneville, A.; Sebert, M.; Eclache, V.; Preudhomme, C.; Mozziconacci, M.-J.; de The, H.; Lehmann-Che, J.; Fenaux, P. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine. Leuk. Res. 2014, 38, 751–755. [Google Scholar] [CrossRef] [PubMed]
  52. Desoutter, J.; Gay, J.; Berthon, C.; Ades, L.; Gruson, B.; Geffroy, S.; Plantier, I.; Marceau, A.; Helevaut, N.; Fernandes, J.; et al. Molecular prognostic factors in acute myeloid leukemia receiving first-line therapy with azacitidine. Leukemia 2016, 30, 1416–1418. [Google Scholar] [CrossRef] [PubMed]
  53. Welch, J.S.; Petti, A.A.; Miller, C.A.; Fronick, C.C.; O’Laughlin, M.; Fulton, R.S.; Wilson, R.K.; Baty, J.D.; Duncavage, E.J.; Tandon, B.; et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N. Engl. J. Med. 2016, 375, 2023–2036. [Google Scholar] [CrossRef]
  54. Martinez-Høyer, S.; Deng, Y.; Parker, J.; Jiang, J.; Mo, A.; Docking, T.R.; Gharaee, N.; Li, J.; Umlandt, P.; Fuller, M.; et al. Loss of lenalidomide-induced megakaryocytic differentiation leads to therapy resistance in del(5q) myelodysplastic syndrome. Nat. Cell Biol. 2020, 22, 526–533. [Google Scholar] [CrossRef]
  55. Wong, T.N.; Ramsingh, G.; Young, A.L.; Miller, C.A.; Touma, W.; Welch, J.S.; Lamprecht, T.L.; Shen, D.; Hundal, J.; Fulton, R.S.; et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 2015, 518, 552–555. [Google Scholar] [CrossRef] [Green Version]
  56. Lindsley, R.C.; Saber, W.; Mar, B.G.; Redd, R.; Wang, T.; Haagenson, M.D.; Grauman, P.V.; Hu, Z.-H.; Spellman, S.R.; Lee, S.J.; et al. Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N. Engl. J. Med. 2017, 376, 536–547. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Genovese, G.; Kähler, A.K.; Handsaker, R.E.; Lindberg, J.; Rose, S.A.; Bakhoum, S.F.; Chambert, K.; Mick, E.; Neale, B.M.; Fromer, M.; et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 2014, 371, 2477–2487. [Google Scholar] [CrossRef] [Green Version]
  58. Jaiswal, S.; Fontanillas, P.; Flannick, J.; Manning, A.; Grauman, P.V.; Mar, B.G.; Lindsley, R.C.; Mermel, C.H.; Burtt, N.; Chavez, A.; et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 2014, 371, 2488–2498. [Google Scholar] [CrossRef] [Green Version]
  59. Coombs, C.C.; Zehir, A.; Devlin, S.M.; Kishtagari, A.; Syed, A.; Jonsson, P.; Hyman, D.M.; Solit, D.B.; Robson, M.E.; Baselga, J.; et al. Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. Cell Stem Cell 2017, 21, 374–382.e4. [Google Scholar] [CrossRef] [Green Version]
  60. Wong, T.N.; Miller, C.A.; Jotte, M.R.M.; Bagegni, N.; Baty, J.D.; Schmidt, A.P.; Cashen, A.F.; Duncavage, E.J.; Helton, N.M.; Fiala, M.; et al. Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat. Commun. 2018, 9, 455. [Google Scholar] [CrossRef] [Green Version]
  61. Chen, S.; Gao, R.; Yao, C.; Kobayashi, M.; Liu, S.Z.; Yoder, M.C.; Broxmeyer, H.; Kapur, R.; Boswell, H.S.; Mayo, L.D.; et al. Genotoxic stresses promote clonal expansion of hematopoietic stem cells expressing mutant p53. Leukemia 2018, 32, 850–854. [Google Scholar] [CrossRef] [PubMed]
  62. Chen, S.; Wang, Q.; Yu, H.; Capitano, M.L.; Vemula, S.; Nabinger, S.C.; Gao, R.; Yao, C.; Kobayashi, M.; Geng, Z.; et al. Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway. Nat. Commun. 2019, 10, 5649. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Chen, S.; Liu, Y. p53 involvement in clonal hematopoiesis of indeterminate potential. Curr. Opin. Hematol. 2019, 26, 235–240. [Google Scholar] [CrossRef] [PubMed]
  64. Miller, P.G.; Steensma, D.P. Implications of Clonal Hematopoiesis for Precision Oncology. JCO Precis. Oncol. 2020, 4, 639–646. [Google Scholar] [CrossRef] [PubMed]
  65. Haferlach, C.; Dicker, F.; Herholz, H.; Schnittger, S.; Kern, W.; Haferlach, T. Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia 2008, 22, 1539–1541. [Google Scholar] [CrossRef]
  66. Bowen, D.; Groves, M.J.; Burnett, A.K.; Patel, Y.; Allen, C.; Green, C.; Gale, R.E.; Hills, R.; Linch, D.C. TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis. Leukemia 2009, 23, 203–206. [Google Scholar] [CrossRef] [Green Version]
  67. Stoddart, A.; Fernald, A.A.; Wang, J.; Davis, E.M.; Karrison, T.; Anastasi, J.; Le Beau, M.M. Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice. Blood 2014, 123, 1069–1078. [Google Scholar] [CrossRef] [Green Version]
  68. Prokocimer, M.; Molchadsky, A.; Rotter, V. Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: Projections on diagnostic workup and therapy. Blood 2017, 130, 699–712. [Google Scholar] [CrossRef] [Green Version]
  69. Harutyunyan, A.; Klampfl, T.; Cazzola, M.; Kralovics, R. p53 lesions in leukemic transformation. N. Engl. J. Med. 2011, 364, 488–490. [Google Scholar] [CrossRef] [Green Version]
  70. Rampal, R.; Ahn, J.; Abdel-Wahab, O.; Nahas, M.; Wang, K.; Lipson, D.; Otto, G.A.; Yelensky, R.; Hricik, T.; McKenney, A.S.; et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc. Natl. Acad. Sci. USA 2014, 111, E5401–E5410. [Google Scholar] [CrossRef] [Green Version]
  71. Ohgami, R.S.; Ma, L.; Merker, J.D.; Gotlib, J.R.; Schrijver, I.; Zehnder, J.L.; Arber, D.A. Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations. Mod. Pathol. 2015, 28, 706–714. [Google Scholar] [CrossRef] [Green Version]
  72. Courtier, F.; Carbuccia, N.; Garnier, S.; Guille, A.; Adélaïde, J.; Cervera, N.; Gelsi-Boyer, V.; Mozziconacci, M.-J.; Rey, J.; Vey, N.; et al. Genomic analysis of myeloproliferative neoplasms in chronic and acute phases. Haematologica 2017, 102, e11–e14. [Google Scholar] [CrossRef] [PubMed]
  73. Kubesova, B.; Pavlova, S.; Malcikova, J.; Kabathova, J.; Radova, L.; Tom, N.; Tichy, B.; Plevova, K.; Kantorova, B.; Fiedorova, K.; et al. Low-burden TP53 mutations in chronic phase of myeloproliferative neoplasms: Association with age, hydroxyurea administration, disease type and JAK2 mutational status. Leukemia 2018, 32, 450–461. [Google Scholar] [CrossRef] [PubMed]
  74. Shlush, L.I.; Zandi, S.; Mitchell, A.; Chen, W.C.; Brandwein, J.M.; Gupta, V.; Kennedy, J.A.; Schimmer, A.D.; Schuh, A.C.; Yee, K.W.; et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014, 506, 328–333. [Google Scholar] [CrossRef] [Green Version]
  75. Corces-Zimmerman, M.R.; Hong, W.-J.; Weissman, I.L.; Medeiros, B.C.; Majeti, R. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc. Natl. Acad. Sci. USA 2014, 111, 2548–2553. [Google Scholar] [CrossRef] [Green Version]
  76. Muller, P.A.J.; Vousden, K.H. Mutant p53 in cancer: New functions and therapeutic opportunities. Cancer Cell 2014, 25, 304–317. [Google Scholar] [CrossRef] [Green Version]
  77. Heuser, M. Therapy-related myeloid neoplasms: Does knowing the origin help to guide treatment? Hematol. Am. Soc. Hematol. Educ. Program 2016, 2016, 24–32. [Google Scholar] [CrossRef]
  78. Lal, R.; Lind, K.; Heitzer, E.; Ulz, P.; Aubell, K.; Kashofer, K.; Middeke, J.M.; Thiede, C.; Schulz, E.; Rosenberger, A.; et al. Somatic TP53 mutations characterize preleukemic stem cells in acute myeloid leukemia. Blood 2017, 129, 2587–2591. [Google Scholar] [CrossRef] [Green Version]
  79. Rausch, T.; Jones, D.T.W.; Zapatka, M.; Stütz, A.M.; Zichner, T.; Weischenfeldt, J.; Jäger, N.; Remke, M.; Shih, D.; Northcott, P.A.; et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 2012, 148, 59–71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Gualberto, A.; Aldape, K.; Kozakiewicz, K.; Tlsty, T.D. An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Proc. Natl. Acad. Sci. USA 1998, 95, 5166–5171. [Google Scholar] [CrossRef] [Green Version]
  81. Olivier, M.; Hollstein, M.; Hainaut, P. TP53 mutations in human cancers: Origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol. 2010, 2, a001008. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Cerami, E.; Gao, J.; Dogrusoz, U.; Gross, B.E.; Sumer, S.O.; Aksoy, B.A.; Jacobsen, A.; Byrne, C.J.; Heuer, M.L.; Larsson, E.; et al. The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012, 2, 401–404. [Google Scholar] [CrossRef] [Green Version]
  83. Gao, J.; Aksoy, B.A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S.O.; Sun, Y.; Jacobsen, A.; Sinha, R.; Larsson, E.; et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 2013, 6, pl1. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Wang, L.-H.; Wu, C.-F.; Rajasekaran, N.; Shin, Y.K. Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview. Cell. Physiol. Biochem. 2018, 51, 2647–2693. [Google Scholar] [CrossRef] [PubMed]
  85. Aubrey, B.J.; Janic, A.; Chen, Y.; Chang, C.; Lieschke, E.C.; Diepstraten, S.T.; Kueh, A.J.; Bernardini, J.P.; Dewson, G.; O’Reilly, L.A.; et al. Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development. Genes Dev. 2018, 32, 1420–1429. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Gencel-Augusto, J.; Lozano, G. p53 tetramerization: At the center of the dominant-negative effect of mutant p53. Genes Dev. 2020, 34, 1128–1146. [Google Scholar] [CrossRef]
  87. Lang, G.A.; Iwakuma, T.; Suh, Y.-A.; Liu, G.; Rao, V.A.; Parant, J.M.; Valentin-Vega, Y.A.; Terzian, T.; Caldwell, L.C.; Strong, L.C.; et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 2004, 119, 861–872. [Google Scholar] [CrossRef] [Green Version]
  88. Olive, K.P.; Tuveson, D.A.; Ruhe, Z.C.; Yin, B.; Willis, N.A.; Bronson, R.T.; Crowley, D.; Jacks, T. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 2004, 119, 847–860. [Google Scholar] [CrossRef] [Green Version]
  89. Doyle, B.; Morton, J.P.; Delaney, D.W.; Ridgway, R.A.; Wilkins, J.A.; Sansom, O.J. p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma. J. Pathol. 2010, 222, 129–137. [Google Scholar] [CrossRef]
  90. Morton, J.P.; Timpson, P.; Karim, S.A.; Ridgway, R.A.; Athineos, D.; Doyle, B.; Jamieson, N.B.; Oien, K.A.; Lowy, A.M.; Brunton, V.G.; et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl. Acad. Sci. USA 2010, 107, 246–251. [Google Scholar] [CrossRef] [Green Version]
  91. Yue, X.; Zhao, Y.; Xu, Y.; Zheng, M.; Feng, Z.; Hu, W. Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy. J. Mol. Biol. 2017, 429, 1595–1606. [Google Scholar] [CrossRef] [PubMed]
  92. Zhang, C.; Liu, J.; Xu, D.; Zhang, T.; Hu, W.; Feng, Z. Gain-of-function mutant p53 in cancer progression and therapy. J. Mol. Cell Biol. 2020, 12, 674–687. [Google Scholar] [CrossRef] [PubMed]
  93. Alvarado-Ortiz, E.; de la Cruz-López, K.G.; Becerril-Rico, J.; Sarabia-Sánchez, M.A.; Ortiz-Sánchez, E.; García-Carrancá, A. Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches. Front. Cell Dev. Biol. 2021, 8, 607670. [Google Scholar] [CrossRef] [PubMed]
  94. Boettcher, S.; Miller, P.G.; Sharma, R.; McConkey, M.; Leventhal, M.; Krivtsov, A.V.; Giacomelli, A.O.; Wong, W.; Kim, J.; Chao, S.; et al. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science 2019, 365, 599–604. [Google Scholar] [CrossRef]
  95. Chen, C.; Liu, Y.; Rappaport, A.R.; Kitzing, T.; Schultz, N.; Zhao, Z.; Shroff, A.S.; Dickins, R.A.; Vakoc, C.R.; Bradner, J.E.; et al. MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 2014, 25, 652–665. [Google Scholar] [CrossRef] [Green Version]
  96. Loizou, E.; Banito, A.; Livshits, G.; Ho, Y.-J.; Koche, R.P.; Sánchez-Rivera, F.J.; Mayle, A.; Chen, C.-C.; Kinalis, S.; Bagger, F.O.; et al. A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1. Cancer Discov. 2019, 9, 962–979. [Google Scholar] [CrossRef] [Green Version]
  97. Liu, Y.; Chen, C.; Xu, Z.; Scuoppo, C.; Rillahan, C.D.; Gao, J.; Spitzer, B.; Bosbach, B.; Kastenhuber, E.R.; Baslan, T.; et al. Deletions linked to TP53 loss drive cancer through p53-independent mechanisms. Nature 2016, 531, 471–475. [Google Scholar] [CrossRef] [Green Version]
  98. Göhring, G.; Giagounidis, A.; Büsche, G.; Kreipe, H.H.; Zimmermann, M.; Hellström-Lindberg, E.; Aul, C.; Schlegelberger, B. Patients with del(5q) MDS who fail to achieve sustained erythroid or cytogenetic remission after treatment with lenalidomide have an increased risk for clonal evolution and AML progression. Ann. Hematol. 2010, 89, 365–374. [Google Scholar] [CrossRef] [Green Version]
  99. Lindsley, R.C.; Gibson, C.J.; Murdock, H.M.; Stone, R.M.; Cortes, J.E.; Uy, G.L.; Lin, T.L.; Ritchie, E.K.; Prebet, T.; Ryan, R.J.; et al. Genetic Characteristics and Outcomes By Mutation Status in a Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Newly Diagnosed, High-Risk/Secondary Acute Myeloid Leukemia (AML). Blood 2019, 134, 15. [Google Scholar] [CrossRef]
  100. DiNardo, C.D.; Jonas, B.A.; Pullarkat, V.; Thirman, M.J.; Garcia, J.S.; Wei, A.H.; Konopleva, M.; Döhner, H.; Letai, A.; Fenaux, P.; et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N. Engl. J. Med. 2020, 383, 617–629. [Google Scholar] [CrossRef]
  101. Britt, A.; Mohyuddin, G.R.; McClune, B.; Singh, A.; Lin, T.; Ganguly, S.; Abhyankar, S.; Shune, L.; McGuirk, J.; Skikne, B.; et al. Acute myeloid leukemia or myelodysplastic syndrome with chromosome 17 abnormalities and long-term outcomes with or without hematopoietic stem cell transplantation. Leuk. Res. 2020, 95, 106402. [Google Scholar] [CrossRef]
  102. Poiré, X.; Labopin, M.; Polge, E.; Forcade, E.; Ganser, A.; Volin, L.; Michallet, M.; Blaise, D.; Yakoub-Agha, I.; Maertens, J.; et al. Allogeneic stem cell transplantation using HLA-matched donors for acute myeloid leukemia with deletion 5q or monosomy 5: A study from the Acute Leukemia Working Party of the EBMT. Haematologica 2020, 105, 414–423. [Google Scholar] [CrossRef] [Green Version]
  103. Garderet, L.; Ziagkos, D.; van Biezen, A.; Iacobelli, S.; Finke, J.; Maertens, J.; Volin, L.; Ljungman, P.; Chevallier, P.; Passweg, J.; et al. Allogeneic Stem Cell Transplantation for Myelodysplastic Syndrome Patients with a 5q Deletion. Biol. Blood Marrow Transplant. 2018, 24, 507–513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Zhang, Q.; Bykov, V.J.N.; Wiman, K.G.; Zawacka-Pankau, J. APR-246 reactivates mutant p53 by targeting cysteines 124 and 277. Cell Death Dis. 2018, 9, 439. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Lambert, J.M.R.; Gorzov, P.; Veprintsev, D.B.; Söderqvist, M.; Segerbäck, D.; Bergman, J.; Fersht, A.R.; Hainaut, P.; Wiman, K.G.; Bykov, V.J.N. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 2009, 15, 376–388. [Google Scholar] [CrossRef] [Green Version]
  106. Peng, X.; Zhang, M.-Q.-Z.; Conserva, F.; Hosny, G.; Selivanova, G.; Bykov, V.J.N.; Arnér, E.S.J.; Wiman, K.G. APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. Cell Death Dis. 2013, 4, e881. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Tessoulin, B.; Descamps, G.; Moreau, P.; Maïga, S.; Lodé, L.; Godon, C.; Marionneau-Lambot, S.; Oullier, T.; Le Gouill, S.; Amiot, M.; et al. PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance. Blood 2014, 124, 1626–1636. [Google Scholar] [CrossRef] [Green Version]
  108. Gourley, C.; Gabra, H.; Vergote, I.; Basu, B.; Brenton, J.; Von Euler, M.; Björklund, U.; Smith, A.M.; Green, J. EUTROC PiSARRO: A phase Ib study combining APR-246 with standard chemotherapy in platinum sensitive relapsed high grade serous ovarian carcinoma (HGSOC). J. Clin. Oncol. 2015, 33, TPS5605. [Google Scholar] [CrossRef]
  109. Sallman, D.A.; DeZern, A.E.; Garcia-Manero, G.; Steensma, D.P.; Roboz, G.J.; Sekeres, M.A.; Cluzeau, T.; Sweet, K.L.; McLemore, A.; McGraw, K.L.; et al. Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes. J. Clin. Oncol. 2021, 39, 1584–1594. [Google Scholar] [CrossRef]
  110. Cluzeau, T.; Sebert, M.; Rahmé, R.; Cuzzubbo, S.; Lehmann-Che, J.; Madelaine, I.; Peterlin, P.; Bève, B.; Attalah, H.; Chermat, F.; et al. Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM). J. Clin. Oncol. 2021, 39, 1575–1583. [Google Scholar] [CrossRef]
  111. Oldenborg, P.-A. CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease. ISRN Hematol. 2013, 2013, 614619. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Murata, Y.; Kotani, T.; Ohnishi, H.; Matozaki, T. The CD47-SIRPα signalling system: Its physiological roles and therapeutic application. J. Biochem. 2014, 155, 335–344. [Google Scholar] [CrossRef] [Green Version]
  113. Jaiswal, S.; Jamieson, C.H.M.; Pang, W.W.; Park, C.Y.; Chao, M.P.; Majeti, R.; Traver, D.; van Rooijen, N.; Weissman, I.L. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 2009, 138, 271–285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Majeti, R.; Chao, M.P.; Alizadeh, A.A.; Pang, W.W.; Jaiswal, S.; Gibbs, K.D.; van Rooijen, N.; Weissman, I.L. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009, 138, 286–299. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Daver, N.; Senapati, J.; Maiti, A.; Loghavi, S.; Kadia, T.M.; DiNardo, C.D.; Pemmaraju, N.; Jabbour, E.; Montalban-Bravo, G.; Tang, G.; et al. Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed (ND) Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML. Blood 2022, 140, 141–144. [Google Scholar] [CrossRef]
  116. Yamaguchi, R.; Lartigue, L.; Perkins, G. Targeting Mcl-1 and other Bcl-2 family member proteins in cancer therapy. Pharmacol. Ther. 2019, 195, 13–20. [Google Scholar] [CrossRef] [PubMed]
  117. Thijssen, R.; Diepstraten, S.T.; Moujalled, D.; Chew, E.; Flensburg, C.; Shi, M.X.; Dengler, M.A.; Litalien, V.; MacRaild, S.; Chen, M.; et al. Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias. Blood 2021, 137, 2721–2735. [Google Scholar] [CrossRef]
  118. Ichim, R.; Lopez, J.; Ahmed, S.U.; Muthalagu, N.; Giampazolias, E.; Delgado, E.M.; Haller, M.; Riley, J.S.; Mason, S.M.; Athineos, D.; et al. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol. Cell 2015, 57, 860–872. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Lopez, J.; Bessou, M.; Riley, J.S.; Giampazolias, E.; Todt, F.; Rochegüe, T.; Oberst, A.; Green, D.R.; Edlich, F.; Ichim, G.; et al. Mito-priming as a method to engineer Bcl-2 addiction. Nat. Commun. 2016, 7, 10538. [Google Scholar] [CrossRef] [Green Version]
  120. Chen, S.; Wu, J.-L.; Liang, Y.; Tang, Y.-G.; Song, H.-X.; Wu, L.-L.; Xing, Y.-F.; Yan, N.; Li, Y.-T.; Wang, Z.-Y.; et al. Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site. Cancer Cell 2021, 39, 225–239.e8. [Google Scholar] [CrossRef]
  121. Weinbach, E.C.; Garbus, J. Mechanism of action of reagents that uncouple oxidative phosphorylation. Nature 1969, 221, 1016–1018. [Google Scholar] [CrossRef] [PubMed]
  122. Al-Hadiya, B.M.H. Niclosamide: Comprehensive profile. Profiles Drug Subst. Excip. Relat. Methodol. 2005, 32, 67–96. [Google Scholar] [PubMed]
  123. Maragos, W.F.; Korde, A.S. Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury. J. Neurochem. 2004, 91, 257–262. [Google Scholar] [CrossRef]
  124. Amara, C.E.; Shankland, E.G.; Jubrias, S.A.; Marcinek, D.J.; Kushmerick, M.J.; Conley, K.E. Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo. Proc. Natl. Acad. Sci. USA 2007, 104, 1057–1062. [Google Scholar] [CrossRef] [Green Version]
  125. Jin, Y.; Lu, Z.; Ding, K.; Li, J.; Du, X.; Chen, C.; Sun, X.; Wu, Y.; Zhou, J.; Pan, J. Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: Inactivation of the NF-kappaB pathway and generation of reactive oxygen species. Cancer Res. 2010, 70, 2516–2527. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Helfman, D.M. Niclosamide: An established antihelminthic drug as a potential therapy against S100A4-mediated metastatic colon tumors. J. Natl. Cancer Inst. 2011, 103, 991–992. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Osada, T.; Chen, M.; Yang, X.Y.; Spasojevic, I.; Vandeusen, J.B.; Hsu, D.; Clary, B.M.; Clay, T.M.; Chen, W.; Morse, M.A.; et al. Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations. Cancer Res. 2011, 71, 4172–4182. [Google Scholar] [CrossRef] [Green Version]
  128. Fonseca, B.D.; Diering, G.H.; Bidinosti, M.A.; Dalal, K.; Alain, T.; Balgi, A.D.; Forestieri, R.; Nodwell, M.; Rajadurai, C.V.; Gunaratnam, C.; et al. Structure-activity analysis of niclosamide reveals potential role for cytoplasmic pH in control of mammalian target of rapamycin complex 1 (mTORC1) signaling. J. Biol. Chem. 2012, 287, 17530–17545. [Google Scholar] [CrossRef] [Green Version]
  129. Arend, R.C.; Londoño-Joshi, A.I.; Gangrade, A.; Katre, A.A.; Kurpad, C.; Li, Y.; Samant, R.S.; Li, P.-K.; Landen, C.N.; Yang, E.S.; et al. Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer. Oncotarget 2016, 7, 86803–86815. [Google Scholar] [CrossRef] [Green Version]
  130. Jin, B.; Wang, C.; Li, J.; Du, X.; Ding, K.; Pan, J. Anthelmintic Niclosamide Disrupts the Interplay of p65 and FOXM1/β-catenin and Eradicates Leukemia Stem Cells in Chronic Myelogenous Leukemia. Clin. Cancer Res. 2017, 23, 789–803. [Google Scholar] [CrossRef] [Green Version]
  131. Kumar, R.; Coronel, L.; Somalanka, B.; Raju, A.; Aning, O.A.; An, O.; Ho, Y.S.; Chen, S.; Mak, S.Y.; Hor, P.Y.; et al. Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers. Nat. Commun. 2018, 9, 3931. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  132. Kaelin, W.G. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 2005, 5, 689–698. [Google Scholar] [CrossRef] [PubMed]
  133. Zhao, D.; Tahaney, W.M.; Mazumdar, A.; Savage, M.I.; Brown, P.H. Molecularly targeted therapies for p53-mutant cancers. Cell. Mol. Life Sci. 2017, 74, 4171–4187. [Google Scholar] [CrossRef] [PubMed]
  134. Gurpinar, E.; Vousden, K.H. Hitting cancers’ weak spots: Vulnerabilities imposed by p53 mutation. Trends Cell Biol. 2015, 25, 486–495. [Google Scholar] [CrossRef]
  135. Kwok, M.; Davies, N.; Agathanggelou, A.; Smith, E.; Oldreive, C.; Petermann, E.; Stewart, G.; Brown, J.; Lau, A.; Pratt, G.; et al. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood 2016, 127, 582–595. [Google Scholar] [CrossRef] [Green Version]
  136. Menendez, D.; Anand, J.R.; Murphy, C.C.; Bell, W.J.; Fu, J.; Slepushkina, N.; Buehler, E.; Martin, S.E.; Lal-Nag, M.; Nitiss, J.L.; et al. Etoposide-induced DNA damage is increased in p53 mutants: Identification of ATR and other genes that influence effects of p53 mutations on Top2-induced cytotoxicity. Oncotarget 2022, 13, 332–346. [Google Scholar] [CrossRef]
  137. Leijen, S.; van Geel, R.M.J.M.; Pavlick, A.C.; Tibes, R.; Rosen, L.; Razak, A.R.A.; Lam, R.; Demuth, T.; Rose, S.; Lee, M.A.; et al. Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors. J. Clin. Oncol. 2016, 34, 4371–4380. [Google Scholar] [CrossRef]
  138. Leijen, S.; van Geel, R.M.J.M.; Sonke, G.S.; de Jong, D.; Rosenberg, E.H.; Marchetti, S.; Pluim, D.; van Werkhoven, E.; Rose, S.; Lee, M.A.; et al. Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months. J. Clin. Oncol. 2016, 34, 4354–4361. [Google Scholar] [CrossRef] [Green Version]
  139. Malekzadeh, P.; Pasetto, A.; Robbins, P.F.; Parkhurst, M.R.; Paria, B.C.; Jia, L.; Gartner, J.J.; Hill, V.; Yu, Z.; Restifo, N.P.; et al. Neoantigen screening identifies broad TP53 mutant immunogenicity in patients with epithelial cancers. J. Clin. Investig. 2019, 129, 1109–1114. [Google Scholar] [CrossRef]
  140. Lo, W.; Parkhurst, M.; Robbins, P.F.; Tran, E.; Lu, Y.-C.; Jia, L.; Gartner, J.J.; Pasetto, A.; Deniger, D.; Malekzadeh, P.; et al. Immunologic Recognition of a Shared p53 Mutated Neoantigen in a Patient with Metastatic Colorectal Cancer. Cancer Immunol. Res. 2019, 7, 534–543. [Google Scholar] [CrossRef]
  141. González-Galarza, F.F.; Takeshita, L.Y.C.; Santos, E.J.M.; Kempson, F.; Maia, M.H.T.; da Silva, A.L.S.; Teles e Silva, A.L.; Ghattaoraya, G.S.; Alfirevic, A.; Jones, A.R.; et al. Allele frequency net 2015 update: New features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations. Nucleic Acids Res. 2015, 43, D784–D788. [Google Scholar] [CrossRef] [PubMed]
  142. Hsiue, E.H.-C.; Wright, K.M.; Douglass, J.; Hwang, M.S.; Mog, B.J.; Pearlman, A.H.; Paul, S.; DiNapoli, S.R.; Konig, M.F.; Wang, Q.; et al. Targeting a neoantigen derived from a common TP53 mutation. Science 2021, 371, eabc8697. [Google Scholar] [CrossRef] [PubMed]
  143. Park, H.; Shapiro, G.I.; Gao, X.; Mahipal, A.; Starr, J.; Furqan, M.; Singh, P.; Ahrorov, A.; Gandhi, L.; Ghosh, A.; et al. Phase Ib study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with advanced or metastatic solid tumors. ESMO Open 2022, 7, 100573. [Google Scholar] [CrossRef] [PubMed]
  144. Mishra, A.; Tamari, R.; DeZern, A.E.; Byrne, M.T.; Gooptu, M.; Chen, Y.-B.; Deeg, H.J.; Sallman, D.; Gallacher, P.; Wennborg, A.; et al. Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes. J. Clin. Oncol. 2022, 40, 3985–3993. [Google Scholar] [CrossRef] [PubMed]
  145. Ray-Coquard, I.; Braicu, I.; Berger, R.; Mahner, S.; Sehouli, J.; Pujade-Lauraine, E.; Cassier, P.A.; Moll, U.M.; Ulmer, H.; Leunen, K.; et al. Part I of GANNET53: A European Multicenter Phase I/II Trial of the Hsp90 Inhibitor Ganetespib Combined With Weekly Paclitaxel in Women With High-Grade, Platinum-Resistant Epithelial Ovarian Cancer-A Study of the GANNET53 Consortium. Front. Oncol. 2019, 9, 832. [Google Scholar] [CrossRef] [PubMed]
  146. Wang, Y.; Janku, F.; Piha-Paul, S.; Hess, K.; Broaddus, R.; Liu, L.; Shi, N.; Overman, M.; Kopetz, S.; Subbiah, V.; et al. Phase I studies of vorinostat with ixazomib or pazopanib imply a role of antiangiogenesis-based therapy for TP53 mutant malignancies. Sci. Rep. 2020, 10, 3080. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Liu, J.F.; Xiong, N.; Campos, S.M.; Wright, A.A.; Krasner, C.; Schumer, S.; Horowitz, N.; Veneris, J.; Tayob, N.; Morrissey, S.; et al. Phase II Study of the WEE1 Inhibitor Adavosertib in Recurrent Uterine Serous Carcinoma. J. Clin. Oncol. 2021, 39, 1531–1539. [Google Scholar] [CrossRef] [PubMed]
  148. Bondar, T.; Medzhitov, R. p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell 2010, 6, 309–322. [Google Scholar] [CrossRef] [Green Version]
  149. Marusyk, A.; Porter, C.C.; Zaberezhnyy, V.; DeGregori, J. Irradiation selects for p53-deficient hematopoietic progenitors. PLoS Biol. 2010, 8, e1000324. [Google Scholar] [CrossRef] [Green Version]
  150. Durkin, S.G.; Glover, T.W. Chromosome fragile sites. Annu. Rev. Genet. 2007, 41, 169–192. [Google Scholar] [CrossRef]
  151. Barlow, J.H.; Faryabi, R.B.; Callén, E.; Wong, N.; Malhowski, A.; Chen, H.T.; Gutierrez-Cruz, G.; Sun, H.-W.; McKinnon, P.; Wright, G.; et al. Identification of early replicating fragile sites that contribute to genome instability. Cell 2013, 152, 620–632. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Bjerregaard, V.A.; Özer, Ö.; Hickson, I.D.; Liu, Y. The Detection and Analysis of Chromosome Fragile Sites. Methods Mol. Biol. 2018, 1672, 471–482. [Google Scholar] [PubMed]
  153. Halazonetis, T.D.; Gorgoulis, V.G.; Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 2008, 319, 1352–1355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Song, H.; Hollstein, M.; Xu, Y. p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. Nat. Cell Biol. 2007, 9, 573–580. [Google Scholar] [CrossRef] [PubMed]
Biomedicines 11 01152 g001 550
Figure 1. A multistep process leads to the development of TP53-mutated myelodysplastic syndrome and acute myeloid leukemia. (A) Hematopoietic stem cells (HSCs) are the only cells within the hematopoietic system that possess the potential for both multipotency (i.e., the potential to differentiate into all of the mature blood cell type) and self-renewal (i.e., the potential to make more stem cells, thus perpetuating the stem cell pool throughout life). Self-renewal is illustrated with red arrows. (B) A mutation in the TP53 gene can emerge in a hematopoietic stem cell (pink nucleus). This mutation can appear spontaneously and is selected in response to various stresses, including exposure to cytotoxic treatments. This mutation can be induced by these cytotoxic treatments (such as chemotherapy or radiation therapy) or by workplace exposure to toxic chemicals and carcinogenic substances such as benzene. (C) Mutant p53 confers a competitive advantage in the stem cell compartment. At this early stage, cells express both wild type and mutant p53 proteins (potential dominant-negative effect). (D) TP53-mutated HSCs acquire chromosomal changes and gene mutations that either result from mutant p53-related genomic instability and chromothripsis, or are induced by cytotoxic chemotherapy/radiation. (E) These acquired genetic changes further enhance the fitness of TP53-mutated HSCs. (F) Further chromosomal changes lead to the loss of the wild type TP53 allele by 17p deletion or monosomy 17. Loss of wild type TP53 functions and potential gain-of-function activities of mutant p53 are responsible for the development of overt acute myeloid leukemia.
Figure 1. A multistep process leads to the development of TP53-mutated myelodysplastic syndrome and acute myeloid leukemia. (A) Hematopoietic stem cells (HSCs) are the only cells within the hematopoietic system that possess the potential for both multipotency (i.e., the potential to differentiate into all of the mature blood cell type) and self-renewal (i.e., the potential to make more stem cells, thus perpetuating the stem cell pool throughout life). Self-renewal is illustrated with red arrows. (B) A mutation in the TP53 gene can emerge in a hematopoietic stem cell (pink nucleus). This mutation can appear spontaneously and is selected in response to various stresses, including exposure to cytotoxic treatments. This mutation can be induced by these cytotoxic treatments (such as chemotherapy or radiation therapy) or by workplace exposure to toxic chemicals and carcinogenic substances such as benzene. (C) Mutant p53 confers a competitive advantage in the stem cell compartment. At this early stage, cells express both wild type and mutant p53 proteins (potential dominant-negative effect). (D) TP53-mutated HSCs acquire chromosomal changes and gene mutations that either result from mutant p53-related genomic instability and chromothripsis, or are induced by cytotoxic chemotherapy/radiation. (E) These acquired genetic changes further enhance the fitness of TP53-mutated HSCs. (F) Further chromosomal changes lead to the loss of the wild type TP53 allele by 17p deletion or monosomy 17. Loss of wild type TP53 functions and potential gain-of-function activities of mutant p53 are responsible for the development of overt acute myeloid leukemia.
Biomedicines 11 01152 g001
Biomedicines 11 01152 g002 550
Figure 2. The special case of myelodysplastic syndrome with 5q deletion. (A) Deletion of 5q chromosome is somatically acquired and heterozygous. This chromosomal abnormality is present in the hematopoietic stem cell compartment and can be found in all lineages. The clinical phenotype of 5q- syndrome (i.e., ineffective erythropoiesis and dysplastic changes) is related to haploinsufficient gene expression of several genes such as RPS14, APC, and EGR1 [67]. Self-renewal is illustrated with red arrows. (B) Monoallelic TP53 mutations are seen at diagnosis in almost 20% of patients with 5q- syndrome, generally at low variant allelic frequency. These mutations are associated with resistance to lenalidomide, but have generally a limited impact on survival. At this stage, karyotype is non-complex [43,44,45,46]. (C) Monoallelic TP53 mutations are associated with genomic instability and chromothripsis in myelodysplastic syndrome with isolated 5q deletion. Progression to higher risk myelodysplastic syndrome and acute myeloid leukemia is preceded by acquisition of a complex karyotype, including 17p deletion and biallelic TP53 inactivation [65,66].
Figure 2. The special case of myelodysplastic syndrome with 5q deletion. (A) Deletion of 5q chromosome is somatically acquired and heterozygous. This chromosomal abnormality is present in the hematopoietic stem cell compartment and can be found in all lineages. The clinical phenotype of 5q- syndrome (i.e., ineffective erythropoiesis and dysplastic changes) is related to haploinsufficient gene expression of several genes such as RPS14, APC, and EGR1 [67]. Self-renewal is illustrated with red arrows. (B) Monoallelic TP53 mutations are seen at diagnosis in almost 20% of patients with 5q- syndrome, generally at low variant allelic frequency. These mutations are associated with resistance to lenalidomide, but have generally a limited impact on survival. At this stage, karyotype is non-complex [43,44,45,46]. (C) Monoallelic TP53 mutations are associated with genomic instability and chromothripsis in myelodysplastic syndrome with isolated 5q deletion. Progression to higher risk myelodysplastic syndrome and acute myeloid leukemia is preceded by acquisition of a complex karyotype, including 17p deletion and biallelic TP53 inactivation [65,66].
Biomedicines 11 01152 g002
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Rahmé, R.; Braun, T.; Manfredi, J.J.; Fenaux, P. TP53 Alterations in Myelodysplastic Syndromes and Acute Myeloid Leukemia. Biomedicines 2023, 11, 1152. https://doi.org/10.3390/biomedicines11041152

AMA Style

Rahmé R, Braun T, Manfredi JJ, Fenaux P. TP53 Alterations in Myelodysplastic Syndromes and Acute Myeloid Leukemia. Biomedicines. 2023; 11(4):1152. https://doi.org/10.3390/biomedicines11041152

Chicago/Turabian Style

Rahmé, Ramy, Thorsten Braun, James J. Manfredi, and Pierre Fenaux. 2023. "TP53 Alterations in Myelodysplastic Syndromes and Acute Myeloid Leukemia" Biomedicines 11, no. 4: 1152. https://doi.org/10.3390/biomedicines11041152

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop