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Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0

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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 May 2020) | Viewed by 54063

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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,

Acute myeloid leukemia (AML) is a highly heterogeneous disease both in terms of its genetic etiology and outcome. In the 1960s, cytogenetic analyses yielded the first insights into the genetic alterations driving its emergence and evolution, and a panel of recurrent chromosome aberrations discovered decades ago still represents one of the main pillars of prognostication. The advent of molecular biology facilitated the discovery and characterization of the fusion genes formed as a consequence of these chromosome rearrangements. In recent years, next-generation sequencing has allowed the establishment of the full inventory of somatically acquired mutations in individuals with AML, as well as the investigation of the evolution of mutational patterns during the course of disease, including treatment, remission, and relapse. In addition to genetic alterations, epigenetic changes and changes in gene expression are of pivotal importance to AML pathogenesis. Together, these studies have identified molecular and genetic alterations that support the diagnosis of AML and facilitate prognostication and disease monitoring. In select cases, they also form the basis for targeted therapies. Indeed, the AML subtype acute promyelocytic leukemia was one of the earliest examples of targeted cancer therapy; all-trans retinoic acid, introduced into the treatment regimen over three decades ago, has impressively improved patient outcome. In the past two years, inhibitors of mutated IDH and FLT3 were approved for use in AML treatment, and several other targeted therapies are under development and hoped to ameliorate the outcome of this aggressive disease in the future.

Another important line of research concerns the role of stem cells in AML. Understanding their roles in disease formation, therapy resistance, and relapse and their interactions with the specific microenvironment of their niche in bone marrow is expected to lead to discoveries that can be exploited therapeutically.

In a recent IJMS Special Issue dedicated to the genetics, biology, and treatment of AML, colleagues contributed valuable articles discussing the genetic hierarchy of AML, the role of measurable residual disease monitoring, relapse of AML after stem cell transplantation, clonal evolution in myelodysplastic syndromes, mouse models of AML, the role of the epigenome in AML with RUNX1-ETO fusions, and therapeutic vulnerabilities in FLT3-mutant AML.

We now welcome additional articles concerning the topics outlined above and/or related to the key words listed below.

Prof. Rotraud Wieser
Guest Editor

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

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

Treatment of AML: chemotherapy, stem cell transplantation, novel therapeutics (approved and under development), immunotherapy
Prognostic significance of genetic and gene expression 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
Mechanisms of therapy resistance and ways to overcome them
AML stem cells and the bone marrow niche
DNA damage and repair in AML
Aberrant transcriptional regulation in AML
mutated/deregulated transcription factors and epigenetic regulators
Aberrant signaling in AML (PI3K, FLT3, WNT, NOTCH, JAK/STAT, etc.)
AML-related fusion genes
microRNAs and other noncoding RNAs in AML
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

Related Special Issue

Genetics, Biology, and Treatment of Acute Myeloid Leukemia in International Journal of Molecular Sciences (9 articles)

Published Papers (11 papers)

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Research

Jump to: Review

19 pages, 2130 KiB

Open AccessArticle

A Screening of Antineoplastic Drugs for Acute Myeloid Leukemia Reveals Contrasting Immunogenic Effects of Etoposide and Fludarabine

by Darina Ocadlikova, Clara Iannarone, Anna Rita Redavid, Michele Cavo and Antonio Curti

Int. J. Mol. Sci. 2020, 21(18), 6802; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186802 - 16 Sep 2020

Cited by 5 | Viewed by 2439

Abstract

Background: Recent evidence demonstrated that the treatment of acute myeloid leukemia (AML) cells with daunorubicin (DNR) but not cytarabine (Ara-C) results in immunogenic cell death (ICD). In the clinical setting, chemotherapy including anthracyclines and Ara-C remains a gold standard for AML treatment. In the last decade, etoposide (Eto) and fludarabine (Flu) have been added to the standard treatment for AML to potentiate its therapeutic effect and have been tested in many trials. Very little data are available about the ability of these drugs to induce ICD. Methods: AML cells were treated with all four drugs. Calreticulin and heat shock protein 70/90 translocation, non-histone chromatin-binding protein high mobility group box 1 and adenosine triphosphate release were evaluated. The treated cells were pulsed into dendritic cells (DCs) and used for in vitro immunological tests. Results: Flu and Ara-C had no capacity to induce ICD-related events. Interestingly, Eto was comparable to DNR in inducing all ICD events, resulting in DC maturation. Moreover, Flu was significantly more potent in inducing suppressive T regulatory cells compared to other drugs. Conclusions: Our results indicate a novel and until now poorly investigated feature of antineoplastic drugs commonly used for AML treatment, based on their different immunogenic potential. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)

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14 pages, 2748 KiB

Open AccessArticle

Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia—A Retrospective Analysis in 337 Patients

by Klaus Geissler, Eva Jäger, Agnes Barna, Michael Gurbisz, Temeida Graf, Elmir Graf, Thomas Nösslinger, Michael Pfeilstöcker, Heinz Tüchler, Thamer Sliwa, Felix Keil, Christoph Geissler, Sonja Heibl, Josef Thaler, Sigrid Machherndl-Spandl, Otto Zach, Ansgar Weltermann, Peter Bettelheim, Reinhard Stauder, Armin Zebisch, Heinz Sill, Ilse Schwarzinger, Bruno Schneeweiss, Leopold Öhler, Ernst Ulsperger, Rajko Kusec, Ulrich Germing, Wolfgang R. Sperr, Paul Knöbl, Ulrich Jäger, Gregor Hörmann and Peter Valent Show full author list Hide full author list

Int. J. Mol. Sci. 2020, 21(8), 3025; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083025 - 24 Apr 2020

Cited by 12 | Viewed by 3094

Abstract

Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, n = 236) and with (B, n = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, n = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% (p < 0.0001), and of high colony growth (≥20/10⁵ peripheral blood mononuclear cells) 31%, 44%, and 80% (p < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)

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23 pages, 3686 KiB

Open AccessArticle

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

by Tobias Gluexam, Alexander M. Grandits, Angela Schlerka, Chi Huu Nguyen, Julia Etzler, Thomas Finkes, Michael Fuchs, Christoph Scheid, Gerwin Heller, Hubert Hackl, Nathalie Harrer, Heinz Sill, Elisabeth Koller, Dagmar Stoiber, Wolfgang Sommergruber and Rotraud Wieser

Int. J. Mol. Sci. 2019, 20(23), 5826; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235826 - 20 Nov 2019

Cited by 21 | Viewed by 3909

Abstract

The neuropeptide CGRP, acting through the G-protein coupled receptor CALCRL and its coreceptor RAMP1, plays a key role in migraines, which has led to the clinical development of several inhibitory compounds. Recently, high CALCRL expression has been shown to be associated with a poor prognosis in acute myeloid leukemia (AML). We investigate, therefore, the functional role of the CGRP-CALCRL axis in AML. To this end, in silico analyses, human AML cell lines, primary patient samples, and a C57BL/6-based mouse model of AML are used. We find that CALCRL is up-regulated at relapse of AML, in leukemic stem cells (LSCs) versus bulk leukemic cells, and in LSCs versus normal hematopoietic stem cells. CGRP protects receptor-positive AML cell lines and primary AML samples from apoptosis induced by cytostatic drugs used in AML therapy, and this effect is inhibited by specific antagonists. Furthermore, the CGRP antagonist olcegepant increases differentiation and reduces the leukemic burden as well as key stem cell properties in a mouse model of AML. These data provide a basis for further investigations into a possible role of CGRP-CALCRL inhibition in the therapy of AML. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)

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Review

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23 pages, 2221 KiB

Open AccessReview

Cutting Edge Molecular Therapy for Acute Myeloid Leukemia

by Kenichi Miyamoto and Yosuke Minami

Int. J. Mol. Sci. 2020, 21(14), 5114; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145114 - 20 Jul 2020

Cited by 4 | Viewed by 4427

Abstract

Recently, whole exome sequencing for acute myeloid leukemia (AML) has been performed by a next-generation sequencer in several studies. It has been revealed that a few gene mutations are identified per AML patient. Some of these mutations are actionable mutations that affect the response to an approved targeted treatment that is available for off-label treatment or that is available in clinical trials. The era of precision medicine for AML has arrived, and it is extremely important to detect actionable mutations relevant to treatment decision-making. However, the percentage of actionable mutations found in AML is about 50% at present, and therapeutic development is also needed for AML patients without actionable mutations. In contrast, the newly approved drugs are less toxic than conventional intensive chemotherapy and can be combined with low-intensity treatments. These combination therapies can contribute to the improvement of prognosis, especially in elderly AML patients who account for more than half of all AML patients. Thus, the treatment strategy for leukemia is changing drastically and showing rapid progress. In this review, we present the latest information regarding the recent development of treatment for AML. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)

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15 pages, 311 KiB

Open AccessReview

The Bone’s Role in Myeloid Neoplasia

by Lukas Kazianka and Philipp B Staber

Int. J. Mol. Sci. 2020, 21(13), 4712; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134712 - 01 Jul 2020

Cited by 1 | Viewed by 2026

Abstract

The interaction of hematopoietic stem and progenitor cells with their direct neighboring cells in the bone marrow (the so called hematopoietic niche) evolves as a key principle for understanding physiological and malignant hematopoiesis. Significant progress in this matter has recently been achieved making use of emerging high-throughput techniques that allow characterization of the bone marrow microenvironment at single cell resolution. This review aims to discuss these single cell findings in the light of other conventional niche studies that together define the current notion of the niche’s implication in (i) normal hematopoiesis, (ii) myeloid neoplasms and (iii) disease-driving pathways that can be exploited to establish novel therapeutic strategies in the future. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)

22 pages, 2663 KiB

Open AccessReview

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

by Ina Nepstad, Kimberley Joanne Hatfield, Ida Sofie Grønningsæter and Håkon Reikvam

Int. J. Mol. Sci. 2020, 21(8), 2907; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082907 - 21 Apr 2020

Cited by 159 | Viewed by 12234

Abstract

Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by uncontrolled proliferation of hematopoietic stem cells in the bone marrow. Malignant cell growth is characterized by disruption of normal intracellular signaling, caused by mutations or aberrant external signaling. The phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway (PI3K-Akt-mTOR pathway) is among one of the intracellular pathways aberrantly upregulated in cancers including AML. Activation of this pathway seems important in leukemogenesis, and given the central role of this pathway in metabolism, the bioenergetics of AML cells may depend on downstream signaling within this pathway. Furthermore, observations suggest that constitutive activation of the PI3K-Akt-mTOR pathway differs between patients, and that increased activity within this pathway is an adverse prognostic parameter in AML. Pharmacological targeting of the PI3K-Akt-mTOR pathway with specific inhibitors results in suppression of leukemic cell growth. However, AML patients seem to differ regarding their susceptibility to various small-molecule inhibitors, reflecting biological heterogeneity in the intracellular signaling status. These findings should be further investigated in both preclinical and clinical settings, along with the potential use of this pathway as a prognostic biomarker, both in patients receiving intensive curative AML treatment and in elderly/unfit receiving AML-stabilizing treatment. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)

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16 pages, 1321 KiB

Open AccessReview

CDK6 Inhibition: A Novel Approach in AML Management

by Iris Z. Uras, Veronika Sexl and Karoline Kollmann

Int. J. Mol. Sci. 2020, 21(7), 2528; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072528 - 05 Apr 2020

Cited by 26 | Viewed by 4809

Abstract

Acute myeloid leukemia (AML) is a complex disease with an aggressive clinical course and high mortality rate. The standard of care for patients has only changed minimally over the past 40 years. However, potentially useful agents have moved from bench to bedside with the potential to revolutionize therapeutic strategies. As such, cell-cycle inhibitors have been discussed as alternative treatment options for AML. In this review, we focus on cyclin-dependent kinase 6 (CDK6) emerging as a key molecule with distinct functions in different subsets of AML. CDK6 exerts its effects in a kinase-dependent and -independent manner which is of clinical significance as current inhibitors only target the enzymatic activity. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)

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20 pages, 299 KiB

Open AccessReview

Acute Myeloid Leukemia in Patients Living with HIV Infection: Several Questions, Fewer Answers

by Fabio Forghieri, Vincenzo Nasillo, Francesca Bettelli, Valeria Pioli, Davide Giusti, Andrea Gilioli, Cristina Mussini, Enrico Tagliafico, Tommaso Trenti, Andrea Cossarizza, Rossana Maffei, Patrizia Barozzi, Leonardo Potenza, Roberto Marasca, Franco Narni and Mario Luppi

Int. J. Mol. Sci. 2020, 21(3), 1081; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031081 - 06 Feb 2020

Cited by 10 | Viewed by 3519

Abstract

Both human immunodeficiency virus (HIV) infection and acute myeloid leukemia (AML) may be considered relatively uncommon disorders in the general population, but the precise incidence of AML in people living with HIV infection (PLWH) is uncertain. However, life expectancy of newly infected HIV-positive patients receiving anti-retroviral therapy (ART) is gradually increasing, rivaling that of age-matched HIV-negative individuals, so that the occurrence of AML is also expected to progressively increase. Even if HIV is not reported to be directly mutagenic, several indirect leukemogenic mechanisms, mainly based on bone marrow microenvironment disruption, have been proposed. Despite a well-controlled HIV infection under ART should no longer be considered per se a contraindication to intensive chemotherapeutic approaches, including allogeneic hematopoietic stem cell transplantation, in selected fit patients with AML, survival outcomes are still generally unsatisfactory. We discussed several controversial issues about pathogenesis and clinical management of AML in PLWH, but few evidence-based answers may currently be provided, due to the limited number of cases reported in the literature, mainly as case reports or small retrospective case series. Prospective multicenter clinical trials are warranted to more precisely investigate epidemiology and cytogenetic/molecular features of AML in PLWH, but also to standardize and further improve its therapeutic management. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)

20 pages, 2105 KiB

Open AccessReview

The Role of Reactive Oxygen Species in Acute Myeloid Leukaemia

by Jonathan R. Sillar, Zacary P. Germon, Geoffry N. De Iuliis and Matthew D. Dun

Int. J. Mol. Sci. 2019, 20(23), 6003; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20236003 - 28 Nov 2019

Cited by 77 | Viewed by 6371

Abstract

Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with a poor overall survival. Reactive oxygen species (ROS) have been shown to be elevated in a wide range of cancers including AML. Whilst previously thought to be mere by-products of cellular metabolism, it is now clear that ROS modulate the function of signalling proteins through oxidation of critical cysteine residues. In this way, ROS have been shown to regulate normal haematopoiesis as well as promote leukaemogenesis in AML. In addition, ROS promote genomic instability by damaging DNA, which promotes chemotherapy resistance. The source of ROS in AML appears to be derived from members of the “NOX family” of NADPH oxidases. Most studies link NOX-derived ROS to activating mutations in the Fms-like tyrosine kinase 3 (FLT3) and Ras-related C3 botulinum toxin substrate (Ras). Targeting ROS through either ROS induction or ROS inhibition provides a novel therapeutic target in AML. In this review, we summarise the role of ROS in normal haematopoiesis and in AML. We also explore the current treatments that modulate ROS levels in AML and discuss emerging drug targets based on pre-clinical work. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)

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13 pages, 856 KiB

Open AccessReview

RAF Kinase Inhibitor Protein in Myeloid Leukemogenesis

by Armin Zebisch, Veronica Caraffini and Heinz Sill

Int. J. Mol. Sci. 2019, 20(22), 5756; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225756 - 16 Nov 2019

Cited by 6 | Viewed by 3328

Abstract

RAF kinase inhibitor protein (RKIP) is an essential regulator of intracellular signaling. A somatic loss of RKIP expression is a frequent event in solid human cancers, and a role of RKIP as metastasis-suppressor is widely accepted nowadays. Recently, RKIP loss has been described in acute myeloid leukemia (AML) and a series of other myeloid neoplasias (MNs). Functional in vitro and in vivo experiments revealed that RKIP is an essential player within the development of these liquid tumors; however, the respective role of RKIP seems to be complex and multi-faceted. In this review, we will summarize the current knowledge about RKIP in myeloid leukemogenesis. We will initially describe its involvement in physiologic hematopoiesis, and will then proceed to discuss its role in the development of AML and other MNs. Finally, we will discuss potential therapeutic implications arising thereof. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)

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20 pages, 943 KiB

Open AccessReview

Aberrant DNA Methylation in Acute Myeloid Leukemia and Its Clinical Implications

by Xianwen Yang, Molly Pui Man Wong and Ray Kit Ng

Int. J. Mol. Sci. 2019, 20(18), 4576; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184576 - 16 Sep 2019

Cited by 52 | Viewed by 7135

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease that is characterized by distinct cytogenetic or genetic abnormalities. Recent discoveries in cancer epigenetics demonstrated a critical role of epigenetic dysregulation in AML pathogenesis. Unlike genetic alterations, the reversible nature of epigenetic modifications is therapeutically attractive in cancer therapy. DNA methylation is an epigenetic modification that regulates gene expression and plays a pivotal role in mammalian development including hematopoiesis. DNA methyltransferases (DNMTs) and Ten-eleven-translocation (TET) dioxygenases are responsible for the dynamics of DNA methylation. Genetic alterations of DNMTs or TETs disrupt normal hematopoiesis and subsequently result in hematological malignancies. Emerging evidence reveals that the dysregulation of DNA methylation is a key event for AML initiation and progression. Importantly, aberrant DNA methylation is regarded as a hallmark of AML, which is heralded as a powerful epigenetic marker in early diagnosis, prognostic prediction, and therapeutic decision-making. In this review, we summarize the current knowledge of DNA methylation in normal hematopoiesis and AML pathogenesis. We also discuss the clinical implications of DNA methylation and the current therapeutic strategies of targeting DNA methylation in AML therapy. Full article

(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)

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