Epigenetics in Myeloproliferative Neoplasms and Acute Myeloid Leukemia

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cellular Pathology".

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Editor


E-Mail Website
Collection Editor
Krukenberg Cancer Center (KKH), University Hospital Halle (Saale), Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany
Interests: myeloproliferative neoplasms; acute myeloid leukemia; epigenetics

Topical Collection Information

Dear Colleagues,

Research over the past years has revealed the increasingly intricate landscape of acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN). Today it is well-appreciated that the heterogeneity of malignant cells in both diseases is triggered by sets of cytogenetic abnormalities and somatic mutations. Besides this genetic complexity, diversification in the epigenome has also been identified as a key player in both tumors. The multidimensional epigenetic picture integrates several layers of (dys)regulated DNA methylation, histone modification, and microRNA modulation. Indeed, abnormal epigenetic signatures, some of which may be linked to specific somatic mutations, frequently present in AML and MPN can profoundly disrupt the phenotype of hematopoietic cells. Furthermore, epigenetic (dys)regulation has emerged as an intersection of several key hallmarks of cancer such as immunology and metabolism.

Thus, understanding the functional link between genetic and epigenetic heterogeneity in AML and MPN, and what they contribute to the disease is an important area of research that would aid clinical decision-making and enhance drug development.

In this Topical Collection, we will discuss the current trends in epigenetic dysregulation in AML and MPN, their interactions with other cancer mechanisms, the interrelation between epigenetics and genetics, and the research on the development of drugs targeting epigenetic regulators, such as IDH1/2 inhibitors and BET proteins, as monotherapies or combination therapies in AML and MPN.

Dr. Haifa Kathrin Al-Ali
Collection Editor

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Keywords

  • AML
  • MPN
  • epigenetics
  • genes
  • mutations
  • therapy
  • DANN methylation
  • histone modification
  • microRNA

Published Papers (5 papers)

2022

Jump to: 2021

15 pages, 1387 KiB  
Review
How Azanucleosides Affect Myeloid Cell Fate
by Anna Stein, Uwe Platzbecker and Michael Cross
Cells 2022, 11(16), 2589; https://doi.org/10.3390/cells11162589 - 19 Aug 2022
Cited by 2 | Viewed by 1740
Abstract
The azanucleosides decitabine and azacytidine are used widely in the treatment of myeloid neoplasia and increasingly in the context of combination therapies. Although they were long regarded as being largely interchangeable in their function as hypomethylating agents, the azanucleosides actually have different mechanisms [...] Read more.
The azanucleosides decitabine and azacytidine are used widely in the treatment of myeloid neoplasia and increasingly in the context of combination therapies. Although they were long regarded as being largely interchangeable in their function as hypomethylating agents, the azanucleosides actually have different mechanisms of action; decitabine interferes primarily with the methylation of DNA and azacytidine with that of RNA. Here, we examine the role of DNA methylation in the lineage commitment of stem cells during normal hematopoiesis and consider how mutations in epigenetic regulators such as DNMT3A and TET2 can lead to clonal expansion and subsequent neoplastic progression. We also consider why the efficacy of azanucleoside treatment is not limited to neoplasias carrying mutations in epigenetic regulators. Finally, we summarise recent data describing a role for azacytidine-sensitive RNA methylation in lineage commitment and in the cellular response to stress. By summarising and interpreting evidence for azanucleoside involvement in a range of cellular processes, our review is intended to illustrate the need to consider multiple modes of action in the design and stratification of future combination therapies. Full article
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24 pages, 4603 KiB  
Article
Diagnostic and Prognostic Power of Active DNA Demethylation Pathway Intermediates in Acute Myelogenous Leukemia and Myelodysplastic Syndromes
by Aleksandra Skalska-Bugala, Marta Starczak, Łukasz Szukalski, Maciej Gawronski, Agnieszka Siomek-Gorecka, Justyna Szpotan, Anna Labejszo, Ewelina Zarakowska, Anna Szpila, Anna Jachalska, Adriana Szukalska, Marcin Kruszewski, Anna Sadowska, Aleksandra Wasilow, Patrycja Baginska, Jaroslaw Czyz, Ryszard Olinski, Rafal Rozalski and Daniel Gackowski
Cells 2022, 11(5), 888; https://doi.org/10.3390/cells11050888 - 4 Mar 2022
Cited by 4 | Viewed by 2320
Abstract
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are characterized by genomic instability, which may arise from the global hypomethylation of the DNA. The active DNA demethylation process may be linked with aberrant methylation and can be involved in leukemogenesis. The levels of [...] Read more.
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are characterized by genomic instability, which may arise from the global hypomethylation of the DNA. The active DNA demethylation process may be linked with aberrant methylation and can be involved in leukemogenesis. The levels of 5-methylcytosine oxidation products were analyzed in minimally invasive material: the cellular DNA from peripheral blood cells and urine of patients with AML and MDS along with the control group, using isotope-dilution two-dimensional ultra-performance liquid chromatography with tandem mass spectrometry. The receiver operating characteristic curve analysis was used for the assessment of the ability to discriminate patients’ groups from the control group, and AML from MDS. The most diagnostically useful for discriminating AML patients from the control group was the urinary excretion of 5-hydroxymethylcytosine (AUC = 0.918, sensitivity: 85%, and specificity: 97%), and 5-(hydroxymethyl)-2′-deoxyuridine (0.873, 74%, and 92%), while for MDS patients 5-(hydroxymethyl)-2′-deoxycytidine in DNA (0.905, 82%, and 98%) and urinary 5-hydroxymethylcytosine (0.746, 66%, and 92%). Multi-factor models of classification trees allowed the correct classification of patients with AML and MDS in 95.7% and 94.7% of cases. The highest prognostic value of the analyzed parameters in predicting the transformation of MDS into AML was observed for 5-carboxy-2′-deoxycytidine (0.823, 80%, and 97%) and 5-(hydroxymethyl)-2′-deoxyuridine (0.872, 100%, and 75%) in DNA. The presented research proves that the intermediates of the active DNA demethylation pathway determined in the completely non-invasive (urine) or minimally invasive (blood) material can be useful in supporting the diagnostic process of patients with MDS and AML. The possibility of an early identification of a group of MDS patients with an increased risk of transformation into AML is of particular importance. Full article
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16 pages, 5649 KiB  
Review
Super-Enhancers Dysregulations in Hematological Malignancies
by Yannis Belloucif and Camille Lobry
Cells 2022, 11(2), 196; https://doi.org/10.3390/cells11020196 - 7 Jan 2022
Cited by 5 | Viewed by 3145
Abstract
Hematological malignancies affecting either the lymphoid or the myeloid lineages involve epigenetic mutations or dysregulation in the majority of cases. These epigenetic abnormalities can affect regulatory elements in the genome and, particularly, enhancers. Recently, large regulatory elements known as super-enhancers, initially identified for [...] Read more.
Hematological malignancies affecting either the lymphoid or the myeloid lineages involve epigenetic mutations or dysregulation in the majority of cases. These epigenetic abnormalities can affect regulatory elements in the genome and, particularly, enhancers. Recently, large regulatory elements known as super-enhancers, initially identified for their critical roles in cell-type specific expression regulation of genes controlling cell identity, have been shown to also be involved in tumorigenesis in many cancer types and hematological malignancies via the regulation of numerous oncogenes, including MYC. In this review, we highlight the existing links between super-enhancers and hematological malignancies, with a particular focus on acute myeloid leukemia, a clonal hematopoietic neoplasm with dismal outcomes, resulting in an uncontrolled proliferation of myeloblasts, abnormally blocked during differentiation and accumulating within the patient’s bone marrow. We report recent works, performed during the last few years, treating this subject and consider the possibility of targeting oncogenic regulatory elements, as well as the effectiveness and limitations reported so far for such strategies. Full article
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2021

Jump to: 2022

18 pages, 1472 KiB  
Review
Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives
by Julian Baumeister, Nicolas Chatain, Alexandros Marios Sofias, Twan Lammers and Steffen Koschmieder
Cells 2021, 10(12), 3551; https://doi.org/10.3390/cells10123551 - 16 Dec 2021
Cited by 25 | Viewed by 7196
Abstract
Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. Progression to more symptomatic disease, such as overt MF or acute leukemia, represents one [...] Read more.
Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. Progression to more symptomatic disease, such as overt MF or acute leukemia, represents one of the major causes of morbidity and mortality. There are clinically evident but also subclinical types of MPN progression. Clinically evident progression includes evolution from ET to PV, ET to post-ET-MF, PV to post-PV-MF, or pre-PMF to overt PMF, and transformation of any of these subtypes to myelodysplastic neoplasms or acute leukemia. Thrombosis, major hemorrhage, severe infections, or increasing symptom burden (e.g., pruritus, night sweats) may herald progression. Subclinical types of progression may include increases in the extent of bone marrow fibrosis, increases of driver gene mutational allele burden, and clonal evolution. The underlying causes of MPN progression are diverse and can be attributed to genetic alterations and chronic inflammation. Particularly, bystander mutations in genes encoding epigenetic regulators or splicing factors were associated with progression. Finally, comorbidities such as systemic inflammation, cardiovascular diseases, and organ fibrosis may augment the risk of progression. The aim of this review was to discuss types and mechanisms of MPN progression and how their knowledge might improve risk stratification and therapeutic intervention. In view of these aspects, we discuss the potential benefits of early diagnosis using molecular and functional imaging and exploitable therapeutic strategies that may prevent progression, but also highlight current challenges and methodological pitfalls. Full article
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19 pages, 2645 KiB  
Article
Integrated N- and O-Glycomics of Acute Myeloid Leukemia (AML) Cell Lines
by Constantin Blöchl, Di Wang, Katarina Madunić, Guinevere S. M. Lageveen-Kammeijer, Christian G. Huber, Manfred Wuhrer and Tao Zhang
Cells 2021, 10(11), 3058; https://doi.org/10.3390/cells10113058 - 6 Nov 2021
Cited by 6 | Viewed by 3262
Abstract
Acute myeloid leukemia (AML) is characterized by a dysregulated expansion of poorly differentiated myeloid cells. Although patients are usually treated effectively by chemotherapy, a high rate of relapsed or refractory disease poses a major hurdle in its treatment. Recently, several studies have proposed [...] Read more.
Acute myeloid leukemia (AML) is characterized by a dysregulated expansion of poorly differentiated myeloid cells. Although patients are usually treated effectively by chemotherapy, a high rate of relapsed or refractory disease poses a major hurdle in its treatment. Recently, several studies have proposed implications of protein glycosylation in the pathobiology of AML including chemoresistance. Accordingly, associations have been found between specific glycan epitopes and the outcome of the disease. To advance this poorly studied field, we performed an exploratory glycomics study characterizing 21 widely used AML cell lines. Exploiting the benefits of porous graphitized carbon chromatography coupled to tandem mass spectrometry (PGC nano-LC-MS2), we qualitatively and quantitatively profiled N- and O-linked glycans. AML cell lines exhibited distinct glycan fingerprints differing in relevant glycan traits correlating with their cellular phenotype as classified by the FAB system. By implementing transcriptomics data, specific glycosyltransferases and hematopoietic transcription factors were identified, which are candidate drivers of the glycan phenotype of these cells. In conclusion, we report the varying expression of glycan structures across a high number of AML cell lines, including those associated with poor prognosis, identified underlying glycosyltransferases and transcription factors, and provide insights into the regulation of the AML glycan repertoire. Full article
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