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Advances in Therapy of Acute Myeloid Leukemia

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 March 2024) | Viewed by 9039

Special Issue Editor


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Guest Editor
Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation Wroclaw Medical University, Pasteur 4 Street, 50-367 Wroclaw, Poland
Interests: acute myeloid leukemia; molecular pathogenesis; targeted therapies; hematology; cancer

Special Issue Information

Dear Colleagues,

Acute myeloid leukemia (AML) is a heterogeneous disease in terms of molecular pathogenesis and clinical manifestation. AML is the most common disorder in adults. Although many patients with AML achieve remission after first induction chemotherapy, relapse and refractory disease occur relatively often and are the cause of death. The AML patient population is highly heterogeneous. Therefore, the treatment of patients with AML should be based on individual risk factors. Until 2017, only acute promyelocytic leukemia (APL) was treated with targeted therapy (all-trans-retinoic acid). In recent years, new targeted therapies have developed in AML. These agents target various cellular processes: signaling pathways, DNA methylation, or chromatin remodeling. The new therapies include FLT3 inhibitors, IDH inhibitors, and Bcl-2 inhibitors. Each of these new therapies has different pharmacological profiles, adverse effects, and levels of effectiveness. A solid knowledge of the molecular basis of AML allows for the conscious application of new therapies. However, there is a large group of AML patients for whom molecular and genetic factors are unknown. Relapsed patients are particularly classified as being at significant risk. It is thus necessary to search for new molecular, genetic, and immunological factors that can play a prognostic role and become the target of new AML therapies in the future.

This Special Issue will be dedicated to new prognostic factors, and new therapies used in AML.

Suitable topics include, but are not limited to:

  • acute myeloid leukemia;
  • new prognostic factors in acute myeloid leukemia;
  • potential targeted therapies;
  • pathogenesis of acute myeloid leukemia.

Dr. Justyna Rybka
Guest Editor

Manuscript Submission Information

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Keywords

  • acute myeloid leukemia
  • prognostic factors
  • molecular pathogenesis
  • experimental therapies

Published Papers (4 papers)

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Research

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21 pages, 5143 KiB  
Article
Cytotoxic Effects of Darinaparsin, a Novel Organic Arsenical, against Human Leukemia Cells
by Bo Yuan, Hidetomo Kikuchi, Jingmei Li, Atsushi Kawabata, Kozo Yao, Norio Takagi and Mari Okazaki
Int. J. Mol. Sci. 2023, 24(3), 2282; https://doi.org/10.3390/ijms24032282 - 23 Jan 2023
Cited by 3 | Viewed by 2184
Abstract
To explore the molecular mechanisms of action underlying the antileukemia activities of darinaparsin, an organic arsenical approved for the treatment of peripheral T–cell lymphoma in Japan, cytotoxicity of darinaparsin was evaluated in leukemia cell lines NB4, U-937, MOLT-4 and HL-60. Darinaparsin was a [...] Read more.
To explore the molecular mechanisms of action underlying the antileukemia activities of darinaparsin, an organic arsenical approved for the treatment of peripheral T–cell lymphoma in Japan, cytotoxicity of darinaparsin was evaluated in leukemia cell lines NB4, U-937, MOLT-4 and HL-60. Darinaparsin was a more potent cytotoxic than sodium arsenite, and induced apoptosis/necrosis in NB4 and HL-60 cells. In NB4 cells exhibiting the highest susceptibility to darinaparsin, apoptosis induction was accompanied by the activation of caspase-8/-9/-3, a substantial decrease in Bid expression, and was suppressed by Boc-D-FMK, a pancaspase inhibitor, suggesting that darinaparsin triggered a convergence of the extrinsic and intrinsic pathways of apoptosis via Bid truncation. A dramatic increase in the expression level of γH2AX, a DNA damage marker, occurred in parallel with G2/M arrest. Activation of p53 and the inhibition of cdc25C/cyclin B1/cdc2 were concomitantly observed in treated cells. Downregulation of c-Myc, along with inactivation of E2F1 associated with the activation of Rb, was observed, suggesting the critical roles of p53 and c-Myc in darinaparsin-mediated G2/M arrest. Trolox, an antioxidative reagent, suppressed the apoptosis induction but failed to correct G2/M arrest, suggesting that oxidative stress primarily contributed to apoptosis induction. Suppression of Notch1 signaling was also confirmed. Our findings provide novel insights into molecular mechanisms underlying the cytotoxicity of darinaparsin and strong rationale for its new clinical application for patients with different types of cancer. Full article
(This article belongs to the Special Issue Advances in Therapy of Acute Myeloid Leukemia)
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12 pages, 3108 KiB  
Article
Polymorphisms in the Genes Coding for TLRs, NLRs and RLRs Are Associated with Clinical Parameters of Patients with Acute Myeloid Leukemia
by Katarzyna Wicherska-Pawłowska, Katarzyna Bogunia-Kubik, Bartłomiej Kuszczak, Piotr Łacina, Marta Dratwa, Bożena Jaźwiec, Tomasz Wróbel and Justyna Rybka
Int. J. Mol. Sci. 2022, 23(17), 9593; https://doi.org/10.3390/ijms23179593 - 24 Aug 2022
Cited by 1 | Viewed by 1262
Abstract
Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) are major elements of the innate immune system that recognize pathogen-associated molecular patterns. Single-nucleotide polymorphisms (SNPs) in the TLR, NLR, and RLR genes may lead to an imbalance in the production of pro- [...] Read more.
Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) are major elements of the innate immune system that recognize pathogen-associated molecular patterns. Single-nucleotide polymorphisms (SNPs) in the TLR, NLR, and RLR genes may lead to an imbalance in the production of pro- and anti-inflammatory cytokines, changes in susceptibility to infections, the development of diseases, and carcinogenesis. Acute myeloid leukemia (AML) is a bone marrow malignancy characterized by uncontrolled proliferation of transformed myeloid precursors. We retrospectively analyzed 90 AML patients. We investigated the effect of fifteen SNPs located in the genes coding for RLR1 (rs9695310, rs10738889, rs10813831), NOD1 (rs2075820, rs6958571), NOD2 (rs2066845, rs2066847, rs2066844), TLR3 (rs5743305, rs3775296, 3775291), TLR4 (rs4986791, rs4986790), and TLR9 (rs187084, rs5743836). We observed that TLR4 rs4986791, TLR9 rs5743836, and NOD2 rs2066847 were associated with CRP levels, while RLR-1 rs10738889 was associated with LDH level. Furthermore, we found TLR3 rs5743305 AA to be more common in patients with infections. We also found TLR9 rs187084 C to be associated with more favorable risk, and RLR-1 rs9695310 GG with higher age at diagnosis. In conclusion, the current study showed that SNPs in the genes encoding TLRs, NLRs, and RLRs may be potential biomarkers in patients with AML. Full article
(This article belongs to the Special Issue Advances in Therapy of Acute Myeloid Leukemia)
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Review

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39 pages, 1251 KiB  
Review
Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia
by Kathryn A. Skelding, Daniel L. Barry, Danielle Z. Theron and Lisa F. Lincz
Int. J. Mol. Sci. 2023, 24(1), 563; https://doi.org/10.3390/ijms24010563 - 29 Dec 2022
Cited by 6 | Viewed by 2368
Abstract
Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among [...] Read more.
Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among stromal, haematopoietic progenitor and leukaemic cells. Traditional therapies targeting leukaemic cells have failed to improve long term survival rates, and as such, the bone marrow niche has become a promising new source of potential therapeutic targets, particularly for relapsed and refractory AML. This review briefly discusses the role of the bone marrow microenvironment in AML development and progression, and as a source of novel therapeutic targets for AML. The main focus of this review is on drugs that modulate/target this bone marrow microenvironment and have been examined in in vivo models or clinically. Full article
(This article belongs to the Special Issue Advances in Therapy of Acute Myeloid Leukemia)
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12 pages, 687 KiB  
Review
The Latest Breakthroughs in Immunotherapy for Acute Myeloid Leukemia, with a Special Focus on NKG2D Ligands
by Stefanie Maurer, Xiaoxuan Zhong, Betsy Deza Prada, John Mascarenhas and Lucas Ferrari de Andrade
Int. J. Mol. Sci. 2022, 23(24), 15907; https://doi.org/10.3390/ijms232415907 - 14 Dec 2022
Cited by 1 | Viewed by 2478
Abstract
Acute myeloid leukemia (AML) is a hematological malignancy characterized by clonal expansion of stem and myeloid progenitor cells. Immunotherapy has revolutionized the care for other cancers such as solid tumors and lymphomas, and has the potential to effectively treat AML. There has been [...] Read more.
Acute myeloid leukemia (AML) is a hematological malignancy characterized by clonal expansion of stem and myeloid progenitor cells. Immunotherapy has revolutionized the care for other cancers such as solid tumors and lymphomas, and has the potential to effectively treat AML. There has been substantial progress in the developments of immunotherapeutic approaches for AML over the last several years, including the development of antibodies that further increase the innate immunogenicity of leukemia cells by the inhibition of NKG2D ligand—particularly MICA and MICB—shedding, chimeric proteins such as IL-15 superagonist that expand natural killer (NK) cells, blockers of immunologic checkpoints such as NKG2A, and chemicals that indirectly increase expression of immune stimulatory proteins in leukemia stem cells. Furthermore, cellular therapies have been designed to enable alloreactive immunity by allogeneic NK cells or target leukemia antigens such as mutated NPM1. These immunotherapeutic approaches have demonstrated remarkable efficacies in preclinical studies and have successfully transitioned to early phase clinical trials, to establish safety and initial signal of clinical activity. Here, we briefly discuss some of the most recent and impactful developments in the AML immunotherapy field and provide our perspectives for the future directions of this exciting and new therapeutic opportunity. Full article
(This article belongs to the Special Issue Advances in Therapy of Acute Myeloid Leukemia)
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