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7.4
5.2
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Cancers
Special Issues
Genetic Findings in Acute Myeloid Leukemia
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Genetic Findings in Acute Myeloid Leukemia

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 20603

Special Issue Editors

Dr. Frederik Damm

E-Mail Website
Guest Editor
Department of Hematology, Oncology, and Tumor Immunology, Charité -Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
Interests: leukemogenesis; genetics; preleukemia; clonal hematopoiesis; clonal dynamics
Prof. Dr. Lars B. Bullinger

E-Mail Website
Guest Editor
Department of Hematology, Oncology, and Tumor Immunology, Charité -Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
Interests: acute leukemia; genetics; clonal evolution; minimial residual disease (MRD)

Special Issue Information

Acute Myeloid Leukemia (AML) is the most common type of acute leukemia in adults. Without treatment, AML inevitably leads to death within a few months. AML is a disease with molecularly heterogeneous neoplasms characterized by symptoms related to pancytopenia and by an accumulation of immature myeloid precursors that is a consequence of a blockage in normal cellular differentiation.

While the therapeutic approach to AML has remained largely unchanged for the past few decades, very potent drugs have now emerged, increasing our therapeutic possibilities to overcome this dismal disease. Small molecules targeting frequent genetic alterations such as mutated FLT3 or IDH1/2, antibody drug conjugates, or BH3 mimetics to promote apoptosis open new avenues for better patient outcomes.

In this Special Issue, we welcome submissions of research and review articles bringing together the highest quality of basic and clinical research on genetic findings in AML. Topics touching molecular mechanisms, (epi-)genetics, pre-leukemia, clonal evolution and heterogeneity, mouse models, mechanisms of immune evasion and relapse, and new therapeutic approaches are invited. 

Dr. Frederik Damm
Prof. Dr. Lars B. Bullinger
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • acute myelid leukemia
  • leukemogenesis
  • genetics
  • preleukemia
  • clonal hematopoiesis
  • clonal evolution
  • minimial residual disease (MRD)
  • new therapy approaches

Published Papers (5 papers)

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Review

22 pages, 3303 KiB  
Review
Refining AML Treatment: The Role of Genetics in Response and Resistance Evaluation to New Agents
by Adriane Halik, Christopher Maximilian Arends, Lars Bullinger, Frederik Damm and Mareike Frick
Cancers 2022, 14(7), 1689; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071689 - 26 Mar 2022
Cited by 6 | Viewed by 3663
Abstract
The number of treatment options for acute myeloid leukemia (AML) has greatly increased since 2017. This development is paralleled by the broad implantation of genetic profiling as an integral part of clinical studies, enabling us to characterize mutation–response, mutation–non-response, or mutation–relapse patterns. The [...] Read more.
The number of treatment options for acute myeloid leukemia (AML) has greatly increased since 2017. This development is paralleled by the broad implantation of genetic profiling as an integral part of clinical studies, enabling us to characterize mutation–response, mutation–non-response, or mutation–relapse patterns. The aim of this review is to provide a concise overview of the current state of knowledge with respect to newly approved AML treatment options and the association of response, relapse and resistance with genetic alterations. Specifically, we will highlight current genetic data regarding FLT3 inhibitors, IDH inhibitors, hypomethylating agents (HMA), the BCL-2 inhibitor venetoclax (VEN), the anti-CD33 antibody conjugate gemtuzumab ozogamicin (GO) and the liposomal dual drug CPX-351. Full article
(This article belongs to the Special Issue Genetic Findings in Acute Myeloid Leukemia)
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30 pages, 907 KiB  
Review
Mouse Models of Frequently Mutated Genes in Acute Myeloid Leukemia
by Sagarajit Mohanty and Michael Heuser
Cancers 2021, 13(24), 6192; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246192 - 08 Dec 2021
Cited by 4 | Viewed by 6240
Abstract
Acute myeloid leukemia is a clinically and biologically heterogeneous blood cancer with variable prognosis and response to conventional therapies. Comprehensive sequencing enabled the discovery of recurrent mutations and chromosomal aberrations in AML. Mouse models are essential to study the biological function of these [...] Read more.
Acute myeloid leukemia is a clinically and biologically heterogeneous blood cancer with variable prognosis and response to conventional therapies. Comprehensive sequencing enabled the discovery of recurrent mutations and chromosomal aberrations in AML. Mouse models are essential to study the biological function of these genes and to identify relevant drug targets. This comprehensive review describes the evidence currently available from mouse models for the leukemogenic function of mutations in seven functional gene groups: cell signaling genes, epigenetic modifier genes, nucleophosmin 1 (NPM1), transcription factors, tumor suppressors, spliceosome genes, and cohesin complex genes. Additionally, we provide a synergy map of frequently cooperating mutations in AML development and correlate prognosis of these mutations with leukemogenicity in mouse models to better understand the co-dependence of mutations in AML. Full article
(This article belongs to the Special Issue Genetic Findings in Acute Myeloid Leukemia)
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19 pages, 597 KiB  
Review
Molecular Minimal Residual Disease Detection in Acute Myeloid Leukemia
by Christian M. Vonk, Adil S. A. Al Hinai, Diana Hanekamp and Peter J. M. Valk
Cancers 2021, 13(21), 5431; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215431 - 29 Oct 2021
Cited by 17 | Viewed by 3059
Abstract
Initial induction chemotherapy to eradicate the bulk of acute myeloid leukemia (AML) cells results in complete remission (CR) in the majority of patients. However, leukemic cells persisting in the bone marrow below the morphologic threshold remain unaffected and have the potential to proliferate [...] Read more.
Initial induction chemotherapy to eradicate the bulk of acute myeloid leukemia (AML) cells results in complete remission (CR) in the majority of patients. However, leukemic cells persisting in the bone marrow below the morphologic threshold remain unaffected and have the potential to proliferate and re-emerge as AML relapse. Detection of minimal/measurable residual disease (MRD) is a promising prognostic marker for AML relapse as it can assess an individual patients’ risk profile and evaluate their response to treatment. With the emergence of molecular techniques, such as next generation sequencing (NGS), a more sensitive assessment of molecular MRD markers is available. In recent years, the detection of MRD by molecular assays and its association with AML relapse and survival has been explored and verified in multiple studies. Although most studies show that the presence of MRD leads to a worse clinical outcome, molecular-based methods face several challenges including limited sensitivity/specificity, and a difficult distinction between mutations that are representative of AML rather than clonal hematopoiesis. This review describes the studies that have been performed using molecular-based assays for MRD detection in the context of other MRD detection approaches in AML, and discusses limitations, challenges and opportunities. Full article
(This article belongs to the Special Issue Genetic Findings in Acute Myeloid Leukemia)
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18 pages, 1537 KiB  
Review
Clonal Architecture and Evolutionary Dynamics in Acute Myeloid Leukemias
by Matthieu Duchmann, Lucie Laplane and Raphael Itzykson
Cancers 2021, 13(19), 4887; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194887 - 29 Sep 2021
Cited by 11 | Viewed by 3011
Abstract
Acute myeloid leukemias (AML) results from the accumulation of genetic and epigenetic alterations, often in the context of an aging hematopoietic environment. The development of high-throughput sequencing—and more recently, of single-cell technologies—has shed light on the intratumoral diversity of leukemic cells. Taking AML [...] Read more.
Acute myeloid leukemias (AML) results from the accumulation of genetic and epigenetic alterations, often in the context of an aging hematopoietic environment. The development of high-throughput sequencing—and more recently, of single-cell technologies—has shed light on the intratumoral diversity of leukemic cells. Taking AML as a model disease, we review the multiple sources of genetic, epigenetic, and functional heterogeneity of leukemic cells and discuss the definition of a leukemic clone extending its definition beyond genetics. After introducing the two dimensions contributing to clonal diversity, namely, richness (number of leukemic clones) and evenness (distribution of clone sizes), we discuss the mechanisms at the origin of clonal emergence (mutation rate, number of generations, and effective size of the leukemic population) and the causes of clonal dynamics. We discuss the possible role of neutral drift, but also of cell-intrinsic and -extrinsic influences on clonal fitness. After reviewing available data on the prognostic role of genetic and epigenetic diversity of leukemic cells on patients’ outcome, we discuss how a better understanding of AML as an evolutionary process could lead to the design of novel therapeutic strategies in this disease. Full article
(This article belongs to the Special Issue Genetic Findings in Acute Myeloid Leukemia)
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16 pages, 2017 KiB  
Review
Chromatin-Spliceosome Mutations in Acute Myeloid Leukemia
by Yotaro Ochi and Seishi Ogawa
Cancers 2021, 13(6), 1232; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061232 - 11 Mar 2021
Cited by 7 | Viewed by 3757
Abstract
Recent genetic studies on large patient cohorts with acute myeloid leukemia (AML) have cataloged a comprehensive list of driver mutations, resulting in the classification of AML into distinct genomic subgroups. Among these subgroups, chromatin-spliceosome (CS)-AML is characterized by mutations in the spliceosome, cohesin [...] Read more.
Recent genetic studies on large patient cohorts with acute myeloid leukemia (AML) have cataloged a comprehensive list of driver mutations, resulting in the classification of AML into distinct genomic subgroups. Among these subgroups, chromatin-spliceosome (CS)-AML is characterized by mutations in the spliceosome, cohesin complex, transcription factors, and chromatin modifiers. Class-defining mutations of CS-AML are also frequently identified in myelodysplastic syndrome (MDS) and secondary AML, indicating the molecular similarity among these diseases. CS-AML is associated with myelodysplasia-related changes in hematopoietic cells and poor prognosis, and, thus, can be treated using novel therapeutic strategies and allogeneic stem cell transplantation. Functional studies of CS-mutations in mice have revealed that CS-mutations typically cause MDS-like phenotypes by altering the epigenetic regulation of target genes. Moreover, multiple CS-mutations often synergistically induce more severe phenotypes, such as the development of lethal MDS/AML, suggesting that the accumulation of many CS-mutations plays a crucial role in the progression of MDS/AML. Indeed, the presence of multiple CS-mutations is a stronger indicator of CS-AML than a single mutation. This review summarizes the current understanding of the genetic and clinical features of CS-AML and the functional roles of driver mutations characterizing this unique category of AML. Full article
(This article belongs to the Special Issue Genetic Findings in Acute Myeloid Leukemia)
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