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Genetics, Biology, and Treatment of Acute Myeloid Leukemia

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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 (31 October 2018) | Viewed by 78487

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Prof. Dr. Rotraud Wieser

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Clinic of Medicine I, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
Interests: acute myeloid leukemia; therapy resistance; relapse; retinoic acid; MECOM; non-coding RNAs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Decades of research have led to the accumulation of substantial knowledge about the etiology, genetics, and molecular and cellular biology of acute myeloid leukemia (AML). AML is known as the epitome of a stem cell driven malignancy, and disease relevant interactions between leukemic stem cells and their specific niche in the bone marrow have been extensively characterized. A number of recurrent molecular and genetic aberrations have been detected and established as drivers and important prognosticators of AML, and several useful mouse models of this disease have been generated and described in great detail.

Despite of these advances, outcome for patients with AML has remained poor, with a majority of them either suffering from primary resistance, or relapsing with refractory disease after initially achieving a remission in response to therapy. For decades, no new drugs for the treatment of AML had permanently reached the market, a spell that appears to have been broken in 2017, in which both new formulations of well-established chemotherapeutic drugs and novel, rationally designed agents were approved for the therapy of AML. In addition, the past few years have seen further important milestones in our basic understanding of AML. Most importantly, advances in sequencing technologies have facilitated quantum leaps in our already substantial knowledge of the genetic etiology of AML. Recent studies have focused increasingly not only on elucidating the pathogenesis, but also the evolution of AML from diagnosis to relapse, of which the latter can be viewed as the embodiment of therapy resistant disease. These developments raise hopes that the pace of discovery of clinically useful novel therapeutics will increase, and improve the outcomes of patients with AML to the impressive extent that has already been seen for one of its subtypes, acute promyelocytic leukemia.

This Special Issue welcomes both original papers and review articles addressing one or several of the
above issues, or of the topics mentioned in the key words listed below.

Prof. Rotraud Wieser
Guest Editor

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

Genetic etiology and history of AML, clonal hematopoiesis of indeterminate significance
Prognostic significance of molecular and genetic alterations present at diagnosis of AML
Kinetics of the molecular response to therapy and its prognostic relevance
Minimal residual disease
Molecular and genetic evolution of AML from diagnosis to relapse
AML stem cells and the bone marrow niche
Aberrant transcriptional regulation in AML; mutated/deregulated transcription factors and epigenetic regulators
Aberrant signalling in AML
microRNAs and other noncoding RNAs in AML
Mechanisms of therapy resistance
DNA damage and repair in AML
Mouse models of AML
Treatment of AML: chemotherapy, stem cell transplantation, novel therapeutics (approved and under development)
Therapy related AML: etiology, molecular and genetic alterations, treatment
APL: molecular biology and treatment
Acquired preleukemic syndromes
Hereditary syndromes associated with increased risk of AML

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Related Special Issue

Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0 in International Journal of Molecular Sciences (11 articles)

Published Papers (9 papers)

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15 pages, 2963 KiB

Open AccessArticle

Therapeutic Vulnerabilities in FLT3-Mutant AML Unmasked by Palbociclib

by Iris Z. Uras, Barbara Maurer, Sofie Nebenfuehr, Markus Zojer, Peter Valent and Veronika Sexl

Int. J. Mol. Sci. 2018, 19(12), 3987; https://doi.org/10.3390/ijms19123987 - 11 Dec 2018

Cited by 12 | Viewed by 5010

Abstract

While significant progress has been made in the treatment of acute myeloid leukemia (AML), not all patients can be cured. Mutated in about 1/3 of de novo AML, the FLT3 receptor tyrosine kinase is an attractive target for drug development, activating mutations of the FLT3 map to the juxtamembrane domain (internal tandem duplications, ITD) or the tyrosine kinase domain (TKD), most frequently at codon D835. While small molecule tyrosine kinase inhibitors (TKI) effectively target ITD mutant forms, those on the TKD are not responsive. Moreover, FLT3 inhibition fails to induce a persistent response in patients due to mutational resistance. More potent compounds with broader inhibitory effects on multiple FLT3 mutations are highly desirable. We describe a critical role of CDK6 in the survival of FLT3⁺ AML cells as palbociclib induced apoptosis not only in FLT3–ITD⁺ cells but also in FLT3–D835Y⁺ cells. Antineoplastic effects were also seen in primary patient-derived cells and in a xenograft model, where therapy effectively suppressed tumor formation in vivo at clinically relevant concentrations. In cells with FLT3–ITD or -TKD mutations, the CDK6 protein not only affects cell cycle progression but also transcriptionally regulates oncogenic kinases mediating intrinsic drug resistance, including AURORA and AKT—a feature not shared by its homolog CDK4. While AKT and AURORA kinase inhibitors have significant therapeutic potential in AML, single agent activity has not been proven overly effective. We describe synergistic combination effects when applying these drugs together with palbociclib which could be readily translated to patients with AML bearing FLT3–ITD or –TKD mutations. Targeting synergistically acting vulnerabilities, with CDK6 being the common denominator, may represent a promising strategy to improve AML patient responses and to reduce the incidence of selection of resistance-inducing mutations. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia)

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10 pages, 1512 KiB

Open AccessCommunication

Routes of Clonal Evolution into Complex Karyotypes in Myelodysplastic Syndrome Patients with 5q Deletion

by Simone Feurstein, Kathrin Thomay, Winfried Hofmann, Guntram Buesche, Hans Kreipe, Felicitas Thol, Michael Heuser, Arnold Ganser, Brigitte Schlegelberger and Gudrun Göhring

Int. J. Mol. Sci. 2018, 19(10), 3269; https://doi.org/10.3390/ijms19103269 - 21 Oct 2018

Cited by 6 | Viewed by 4313

Abstract

Myelodysplastic syndrome (MDS) can easily transform into acute myeloid leukemia (AML), a process which is often associated with clonal evolution and development of complex karyotypes. Deletion of 5q (del(5q)) is the most frequent aberration in complex karyotypes. This prompted us to analyze clonal evolution in MDS patients with del(5q). There were 1684 patients with low and intermediate-risk MDS and del(5q) with or without one additional cytogenetic abnormality, who were investigated cytogenetically in our department, involving standard karyotyping, fluorescence in situ hybridization (FISH) and multicolor FISH. We identified 134 patients (8%) with aspects of clonal evolution. There are two main routes of cytogenetic clonal evolution: a stepwise accumulation of cytogenetic events over time and a catastrophic event, which we defined as the occurrence of two or more aberrations present at the same time, leading to a sudden development of highly complex clones. Of the 134 patients, 61% underwent a stepwise accumulation of events whereas 39% displayed a catastrophic event. Patients with isolated del(5q) showed significantly more often a stepwise accumulation of events rather than a catastrophic event. The most frequent aberrations in the group of stepwise accumulation were trisomy 8 and trisomy 21 which were significantly more frequent in this group compared to the catastrophic event group. In the group with catastrophic events, del(7q)/-7 and del(17p)/-17 were the most common aberrations. A loss of 17p, containing the tumor suppressor gene TP53, was found significantly more frequent in this group compared to the group of stepwise accumulation. This leads to the assumption that the loss of TP53 is the driving force in patients with del(5q) who undergo a sudden catastrophic event and evolve into complex karyotypes. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia)

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Review

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11 pages, 915 KiB

Open AccessReview

Roles of SETD2 in Leukemia—Transcription, DNA-Damage, and Beyond

by Anna Skucha, Jessica Ebner and Florian Grebien

Int. J. Mol. Sci. 2019, 20(5), 1029; https://doi.org/10.3390/ijms20051029 - 27 Feb 2019

Cited by 53 | Viewed by 10804

Abstract

The non-redundant histone methyltransferase SETD2 (SET domain containing 2; KMT3A) is responsible for tri-methylation of lysine 36 on histone H3 (H3K36me3). Presence of the H3K36me3 histone mark across the genome has been correlated with transcriptional activation and elongation, but also with the regulation of DNA mismatch repair, homologous recombination and alternative splicing. The role of SETD2 and the H3K36me3 histone mark in cancer is controversial. SETD2 is lost or mutated in various cancers, supporting a tumor suppressive role of the protein. Alterations in the SETD2 gene are also present in leukemia patients, where they are associated with aggressive disease and relapse. In line, heterozygous SETD2 loss caused chemotherapy resistance in leukemia cell lines and mouse models. In contrast, other studies indicate that SETD2 is critically required for the proliferation of leukemia cells. Thus, although studies of SETD2-dependent processes in cancer have contributed to a better understanding of the SETD2–H3K36me3 axis, many open questions remain regarding its specific role in leukemia. Here, we review the current literature about critical functions of SETD2 in the context of hematopoietic malignancies. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia)

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18 pages, 2418 KiB

Open AccessReview

Clonal Hematopoiesis with Oncogenic Potential (CHOP): Separation from CHIP and Roads to AML

by Peter Valent, Wolfgang Kern, Gregor Hoermann, Jelena D. Milosevic Feenstra, Karl Sotlar, Michael Pfeilstöcker, Ulrich Germing, Wolfgang R. Sperr, Andreas Reiter, Dominik Wolf, Michel Arock, Torsten Haferlach and Hans-Peter Horny

Int. J. Mol. Sci. 2019, 20(3), 789; https://doi.org/10.3390/ijms20030789 - 12 Feb 2019

Cited by 52 | Viewed by 7250

Abstract

The development of leukemia is a step-wise process that is associated with molecular diversification and clonal selection of neoplastic stem cells. Depending on the number and combinations of lesions, one or more sub-clones expand/s after a variable latency period. Initial stages may develop early in life or later in adulthood and include premalignant (indolent) stages and the malignant phase, defined by an acute leukemia. We recently proposed a cancer model in which the earliest somatic lesions are often age-related early mutations detectable in apparently healthy individuals and where additional oncogenic mutations will lead to the development of an overt neoplasm that is usually a preleukemic condition such as a myelodysplastic syndrome. These neoplasms may or may not transform to overt acute leukemia over time. Thus, depending on the type and number of somatic mutations, clonal hematopoiesis (CH) can be divided into CH with indeterminate potential (CHIP) and CH with oncogenic potential (CHOP). Whereas CHIP mutations per se usually create the molecular background of a neoplastic process, CHOP mutations are disease-related or even disease-specific lesions that trigger differentiation and/or proliferation of neoplastic cells. Over time, the acquisition of additional oncogenic events converts preleukemic neoplasms into secondary acute myeloid leukemia (sAML). In the present article, recent developments in the field are discussed with a focus on CHOP mutations that lead to distinct myeloid neoplasms, their role in disease evolution, and the impact of additional lesions that can drive a preleukemic neoplasm into sAML. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia)

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27 pages, 5930 KiB

Open AccessReview

Murine Models of Acute Myeloid Leukaemia

by Marwa Almosailleakh and Juerg Schwaller

Int. J. Mol. Sci. 2019, 20(2), 453; https://doi.org/10.3390/ijms20020453 - 21 Jan 2019

Cited by 47 | Viewed by 14670

Abstract

Acute myeloid leukaemia (AML) is a rare but severe form of human cancer that results from a limited number of functionally cooperating genetic abnormalities leading to uncontrolled proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Before the identification of genetic driver lesions, chemically, irradiation or viral infection-induced mouse leukaemia models provided platforms to test novel chemotherapeutics. Later, transgenic mouse models were established to test the in vivo transforming potential of newly cloned fusion genes and genetic aberrations detected in patients’ genomes. Hereby researchers constitutively or conditionally expressed the respective gene in the germline of the mouse or reconstituted the hematopoietic system of lethally irradiated mice with bone marrow virally expressing the mutation of interest. More recently, immune deficient mice have been explored to study patient-derived human AML cells in vivo. Unfortunately, although complementary to each other, none of the currently available strategies faithfully model the initiation and progression of the human disease. Nevertheless, fast advances in the fields of next generation sequencing, molecular technology and bioengineering are continuously contributing to the generation of better mouse models. Here we review the most important AML mouse models of each category, briefly describe their advantages and limitations and show how they have contributed to our understanding of the biology and to the development of novel therapies. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia)

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17 pages, 1013 KiB

Open AccessReview

RUNX1-ETO: Attacking the Epigenome for Genomic Instable Leukemia

by Emiel van der Kouwe and Philipp Bernhard Staber

Int. J. Mol. Sci. 2019, 20(2), 350; https://doi.org/10.3390/ijms20020350 - 16 Jan 2019

Cited by 14 | Viewed by 5937

Abstract

Oncogenic fusion protein RUNX1-ETO is the product of the t(8;21) translocation, responsible for the most common cytogenetic subtype of acute myeloid leukemia. RUNX1, a critical transcription factor in hematopoietic development, is fused with almost the entire ETO sequence with the ability to recruit a wide range of repressors. Past efforts in providing a comprehensive picture of the genome-wide localization and the target genes of RUNX1-ETO have been inconclusive in understanding the underlying mechanism by which it deregulates native RUNX1. In this review; we dissect the current data on the epigenetic impact of RUNX1 and RUNX1-ETO. Both share similarities however, in recent years, research focused on epigenetic factors to explain their differences. RUNX1-ETO impairs DNA repair mechanisms which compromises genomic stability and favors a mutator phenotype. Among an increasing pool of mutated factors, regulators of DNA methylation are frequently found in t(8;21) AML. Together with the alteration of both, histone markers and distal enhancer regulation, RUNX1-ETO might specifically disrupt normal chromatin structure. Epigenetic studies on the fusion protein uncovered new mechanisms contributing to leukemogenesis and hopefully will translate into clinical applications. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia)

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20 pages, 923 KiB

Open AccessReview

Relapse of Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation: Prevention, Detection, and Treatment

by Christina Rautenberg, Ulrich Germing, Rainer Haas, Guido Kobbe and Thomas Schroeder

Int. J. Mol. Sci. 2019, 20(1), 228; https://doi.org/10.3390/ijms20010228 - 8 Jan 2019

Cited by 94 | Viewed by 14095

Abstract

Acute myeloid leukemia (AML) is a phenotypically and prognostically heterogeneous hematopoietic stem cell disease that may be cured in eligible patients with intensive chemotherapy and/or allogeneic stem cell transplantation (allo-SCT). Tremendous advances in sequencing technologies have revealed a large amount of molecular information which has markedly improved our understanding of the underlying pathophysiology and enables a better classification and risk estimation. Furthermore, with the approval of the FMS-like tyrosine kinase 3 (FLT3) inhibitor Midostaurin a first targeted therapy has been introduced into the first-line therapy of younger patients with FLT3-mutated AML and several other small molecules targeting molecular alterations such as isocitrate dehydrogenase (IDH) mutations or the anti-apoptotic b-cell lymphoma 2 (BCL-2) protein are currently under investigation. Despite these advances, many patients will have to undergo allo-SCT during the course of disease and depending on disease and risk status up to half of them will finally relapse after transplant. Here we review the current knowledge about the molecular landscape of AML and how this can be employed to prevent, detect and treat relapse of AML after allo-SCT. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia)

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21 pages, 1367 KiB

Open AccessReview

Genetic Hierarchy of Acute Myeloid Leukemia: From Clonal Hematopoiesis to Molecular Residual Disease

by Jean-Alain Martignoles, François Delhommeau and Pierre Hirsch

Int. J. Mol. Sci. 2018, 19(12), 3850; https://doi.org/10.3390/ijms19123850 - 3 Dec 2018

Cited by 25 | Viewed by 8218

Abstract

Recent advances in the field of cancer genome analysis revolutionized the picture we have of acute myeloid leukemia (AML). Pan-genomic studies, using either single nucleotide polymorphism arrays or whole genome/exome next generation sequencing, uncovered alterations in dozens of new genes or pathways, intimately connected with the development of leukemia. From a simple two-hit model in the late nineties, we are now building clonal stories that involve multiple unexpected cellular functions, leading to full-blown AML. In this review, we will address several seminal concepts that result from these new findings. We will describe the genetic landscape of AML, the association and order of events that define multiple sub-entities, both in terms of pathogenesis and in terms of clinical practice. Finally, we will discuss the use of this knowledge in the settings of new strategies for the evaluation of measurable residual diseases (MRD), using clone-specific multiple molecular targets. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia)

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33 pages, 332 KiB

Open AccessReview

Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

by Fabio Forghieri, Patrizia Comoli, Roberto Marasca, Leonardo Potenza and Mario Luppi

Int. J. Mol. Sci. 2018, 19(11), 3492; https://doi.org/10.3390/ijms19113492 - 6 Nov 2018

Cited by 56 | Viewed by 7020

Abstract

Acute myeloid leukemia (AML) with NPM1 gene mutations is currently recognized as a distinct entity, due to its unique biological and clinical features. We summarize here the results of published studies investigating the clinical application of minimal/measurable residual disease (MRD) in patients with NPM1-mutated AML, receiving either intensive chemotherapy or hematopoietic stem cell transplantation. Several clinical trials have so far demonstrated a significant independent prognostic impact of molecular MRD monitoring in NPM1-mutated AML and, accordingly, the Consensus Document from the European Leukemia Net MRD Working Party has recently recommended that NPM1-mutated AML patients have MRD assessment at informative clinical timepoints during treatment and follow-up. However, several controversies remain, mainly with regard to the most clinically significant timepoints and the MRD thresholds to be considered, but also with respect to the optimal source to be analyzed, namely bone marrow or peripheral blood samples, and the correlation of MRD with other known prognostic indicators. Moreover, we discuss potential advantages, as well as drawbacks, of newer molecular technologies such as digital droplet PCR and next-generation sequencing in comparison to conventional RQ-PCR to quantify NPM1-mutated MRD. In conclusion, further prospective clinical trials are warranted to standardize MRD monitoring strategies and to optimize MRD-guided therapeutic interventions in NPM1-mutated AML patients. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia)

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