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Recent Advances in the Understanding of Myelodysplastic Syndrome and Acute Myeloid Leukemia

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (28 October 2024) | Viewed by 27074

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Special Issue Editors

Dr. Ioannis Mitroulis

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Guest Editor

First Department of Internal Medicine, Democritus University of Thrace, Komotini, Greece
Interests: hematopoietic stem cells; hematopoietic stem cell niche; myelopoiesis; neutrophils; neutrophil extracellular traps; thrombosis; myelodysplastic syndrome

Dr. Konstantinos Liapis

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Guest Editor

Department of Hematology, Democritus University of Thrace, Alexandroupolis, Greece
Interests: myelodysplastic syndrome; hematopoietic stem cell transplantation

Dr. Eleni Gavriilaki

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Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
Interests: hematologic malignancies; thrombosis; complement; cellular therapy; lymphoma; myeloma; COVID-19
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Special Issue Information

Dear Colleagues,

During recent decades, significant progress has been made in the molecular characterization of myeloid malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and myeloproliferative neoplasms (MPN). The technological progress made the identification of several driver mutations feasible, which paves the road for a personalized approach in the diagnosis and treatment of these disorders, as well as in the introduction of targeted therapies in the clinical practice.

Despite the fundamental discoveries in deciphering the genetic basis of myeloid malignancies and the interaction between clonal cells and the bone marrow micro-environment, the treatment of this disorder remained until recently unchanged. For instance, the treatment of patients with low-risk MDS is still largely supportive, using growth factors and transfusions to improve the symptoms of the disease, whereas hypomethylating agents are used in the treatment of older patients with advanced MDS and AML. Based on the aging population, the prevalence of these disorders is expected to increase in the following years.

The aim of this Special Issue is to discuss recent findings in the epidemiology, treatment, and pathogenesis of MDS and AML. Epidemiological studies, clinical trials involving the introduction of novel treatment strategies in MDS and AML, original translational research articles and reviews are welcome in this Special Issue.

We look forward to receiving your contributions.

Dr. Ioannis Mitroulis
Dr. Konstantinos Liapis
Dr. Eleni Gavriilaki
Guest Editors

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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 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.

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Keywords

myelodysplastic syndrome
acute myeloid leukemia
bone marrow microenvironment
targeted therapies
hematopoietic stem cell
leukemic stem cell
hematopoietic stem cell transplantation

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Published Papers (9 papers)

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Research

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10 pages, 2280 KiB

Open AccessCommunication

Growth Charts for Shwachman–Diamond Syndrome at Ages 0 to 18 Years

by Anna Pegoraro, Valentino Bezzerri, Gloria Tridello, Cecilia Brignole, Francesca Lucca, Emily Pintani, Cesare Danesino, Simone Cesaro, Francesca Fioredda and Marco Cipolli

Cancers 2024, 16(7), 1420; https://doi.org/10.3390/cancers16071420 - 5 Apr 2024

Viewed by 1643

Abstract

Shwachman–Diamond syndrome (SDS) is one of the most common inherited bone marrow failure syndromes. SDS is characterized by hypocellular bone marrow, with a severe impairment of the myeloid lineage, resulting in neutropenia, thrombocytopenia, and, more rarely, anemia. Almost 15% of patients with SDS develop myelodysplastic syndrome or acute myeloid leukemia as early as childhood or young adulthood. Exocrine pancreatic insufficiency is another common feature of SDS. Almost all patients with SDS show failure to thrive, which is associated with skeletal abnormalities due to defective ossification. Considering these observations, it remains unfeasible to use the common growth charts already available for the general population. To address this issue, we report how we drew up growth charts of patients with SDS aged 0 to 18 years. We analyzed height, weight, and body max index (BMI) in 121 Italian patients with SDS. Results indicated that the 50th and 3rd percentiles of weight and height of the pediatric general population correspond to the 97th and 50th percentiles of patients with SDS aged 0–18 years, respectively. In addition, the percentage increment in weight of subjects aged 14–18 years was higher in patients with SDS than in the general population. SDS-specific growth charts, such as those described here, afford a new tool, which is potentially useful for both clinical and research purposes in SDS. Full article

(This article belongs to the Special Issue Recent Advances in the Understanding of Myelodysplastic Syndrome and Acute Myeloid Leukemia)

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23 pages, 2420 KiB

Open AccessArticle

Understanding WT1 Alterations and Expression Profiles in Hematological Malignancies

by Naghmeh Niktoreh, Lisa Weber, Christiane Walter, Mahshad Karimifard, Lina Marie Hoffmeister, Hannah Breiter, Aniththa Thivakaran, Maren Soldierer, Hans Günther Drexler, Heiner Schaal, Stephanie Sendker, Dirk Reinhardt, Markus Schneider and Helmut Hanenberg

Cancers 2023, 15(13), 3491; https://doi.org/10.3390/cancers15133491 - 4 Jul 2023

Cited by 3 | Viewed by 2312

Abstract

WT1 is a true chameleon, both acting as an oncogene and tumor suppressor. As its exact role in leukemogenesis is still ambiguous, research with model systems representing natural conditions surrounding the genetic alterations in WT1 is necessary. In a cohort of 59 leukemia/lymphoma cell lines, we showed aberrant expression for WT1 mRNA, which does not always translate into protein levels. We also analyzed the expression pattern of the four major WT1 protein isoforms in the cell lines and primary AML blasts with/without WT1 mutations and demonstrated that the presence of mutations does not influence these patterns. By introduction of key intronic and exonic sequences of WT1 into a lentiviral expression vector, we developed a unique tool that can stably overexpress the four WT1 isoforms at their naturally occurring tissue-dependent ratio. To develop better cellular model systems for WT1, we sequenced large parts of its gene locus and also other important myeloid risk factor genes and revealed previously unknown alterations. Functionally, inhibition of the nonsense-mediated mRNA decay machinery revealed that under natural conditions, the mutated WT1 alleles go through a robust degradation. These results offer new insights and model systems regarding the characteristics of WT1 in leukemia and lymphoma. Full article

(This article belongs to the Special Issue Recent Advances in the Understanding of Myelodysplastic Syndrome and Acute Myeloid Leukemia)

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21 pages, 3226 KiB

Open AccessArticle

Real-World Data on Chronic Myelomonocytic Leukemia: Clinical and Molecular Characteristics, Treatment, Emerging Drugs, and Patient Outcomes

by Sandra Castaño-Díez, Mónica López-Guerra, Cristina Bosch-Castañeda, Alex Bataller, Paola Charry, Daniel Esteban, Francesca Guijarro, Carlos Jiménez-Vicente, Carlos Castillo-Girón, Albert Cortes, Alexandra Martínez-Roca, Ana Triguero, José Ramón Álamo, Silvia Beà, Dolors Costa, Dolors Colomer, María Rozman, Jordi Esteve and Marina Díaz-Beyá

Cancers 2022, 14(17), 4107; https://doi.org/10.3390/cancers14174107 - 25 Aug 2022

Cited by 9 | Viewed by 4086

Abstract

Despite emerging molecular information on chronic myelomonocytic leukemia (CMML), patient outcome remains unsatisfactory and little is known about the transformation to acute myeloid leukemia (AML). In a single-center cohort of 219 CMML patients, we explored the potential correlation between clinical features, gene mutations, and treatment regimens with overall survival (OS) and clonal evolution into AML. The most commonly detected mutations were TET2, SRSF2, ASXL1, and RUNX1. Median OS was 34 months and varied according to age, cytogenetic risk, FAB, CPSS and CPSS-Mol categories, and number of gene mutations. Hypomethylating agents were administered to 37 patients, 18 of whom responded. Allogeneic stem cell transplantation (alloSCT) was performed in 22 patients. Two-year OS after alloSCT was 60.6%. Six patients received targeted therapy with IDH or FLT3 inhibitors, three of whom attained a long-lasting response. AML transformation occurred in 53 patients and the analysis of paired samples showed changes in gene mutation status. Our real-world data emphasize that the outcome of CMML patients is still unsatisfactory and alloSCT remains the only potentially curative treatment. However, targeted therapies show promise in patients with specific gene mutations. Complete molecular characterization can help to improve risk stratification, understand transformation, and personalize therapy. Full article

(This article belongs to the Special Issue Recent Advances in the Understanding of Myelodysplastic Syndrome and Acute Myeloid Leukemia)

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15 pages, 703 KiB

Open AccessReview

The Challenge for a Correct Diagnosis of Refractory Thrombocytopenia: ITP or MDS with Isolated Thrombocytopenia?

by Aikaterini Kosmidou, Eleni Gavriilaki and Athanasios Tragiannidis

Cancers 2024, 16(8), 1462; https://doi.org/10.3390/cancers16081462 - 11 Apr 2024

Viewed by 1961

Abstract

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia. It is diagnosed in patients with a platelet count below 100,000 per cubic millimeter in whom other causes of thrombocytopenia have been ruled out, and its diagnosis is generally one of exclusion. Clinical manifestations of patients may vary from asymptomatic disease to mild mucocutaneous or life-threatening bleeding. Glucocorticoids are used as first-line treatment for ITP, while other second-line medications, mainly thrombopoietin-receptor agonists (TPO-RA) and rituximab, are given to patients in whom ITP does not remit, or relapses soon after glucocorticoid treatment. Refractoriness of ITP strongly questions its diagnosis and necessitates a thorough clinical and laboratory work-up to decide whether that is the case of refractory ITP or a misdiagnosis. The aim of this review is to summarize the conditions associated with isolated thrombocytopenia and highlight the characteristics of confusing cases. Even though the case of a myelodysplastic syndrome presented with isolated thrombocytopenia (MDS-IT) is relatively rare and not well-established in the literature, it constitutes one of the most predominant misdiagnoses of refractory ITP. MDS-IT patients are thought to present with multilineage dysplasia, normal karyotype and low risk prognostic score, based on IPSS-R. It has been shown that a significant proportion of MDS-IT patients are misdiagnosed as having the more common ITP. Therefore, it is crucial that in confusing cases of persistent thrombocytopenia a detailed diagnostic work-up is applied—including evaluation of peripheral-blood smear, bone marrow examination and cytogenetic testing—to avoid unnecessary therapy delay. Full article

(This article belongs to the Special Issue Recent Advances in the Understanding of Myelodysplastic Syndrome and Acute Myeloid Leukemia)

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18 pages, 890 KiB

Open AccessReview

The Role of Non-Coding RNAs in Myelodysplastic Neoplasms

by Vasileios Georgoulis, Epameinondas Koumpis and Eleftheria Hatzimichael

Cancers 2023, 15(19), 4810; https://doi.org/10.3390/cancers15194810 - 30 Sep 2023

Viewed by 2404

Abstract

Myelodysplastic syndromes or neoplasms (MDS) are a heterogeneous group of myeloid clonal disorders characterized by peripheral blood cytopenias, blood and marrow cell dysplasia, and increased risk of evolution to acute myeloid leukemia (AML). Non-coding RNAs, especially microRNAs and long non-coding RNAs, serve as regulators of normal and malignant hematopoiesis and have been implicated in carcinogenesis. This review presents a comprehensive summary of the biology and role of non-coding RNAs, including the less studied circRNA, siRNA, piRNA, and snoRNA as potential prognostic and/or predictive biomarkers or therapeutic targets in MDS. Full article

(This article belongs to the Special Issue Recent Advances in the Understanding of Myelodysplastic Syndrome and Acute Myeloid Leukemia)

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24 pages, 859 KiB

Open AccessReview

Definitions, Biology, and Current Therapeutic Landscape of Myelodysplastic/Myeloproliferative Neoplasms

by Margo B. Gerke, Ilias Christodoulou and Theodoros Karantanos

Cancers 2023, 15(15), 3815; https://doi.org/10.3390/cancers15153815 - 27 Jul 2023

Cited by 9 | Viewed by 3193

Abstract

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hematological disorders characterized by both proliferative and dysplastic features. According to the 2022 International Consensus Classification (ICC), MDS/MPN consists of clonal monocytosis of undetermined significance (CMUS), chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN with SF3B1 mutation (MDS/MPN-T-SF3B1), MDS/MPN with ring sideroblasts and thrombocytosis not otherwise specified (MDS/MPN-RS-T-NOS), and MDS/MPN-NOS. These disorders exhibit a diverse range of genetic alterations involving various transcription factors (e.g., RUNX1), signaling molecules (e.g., NRAS, JAK2), splicing factors (e.g., SF3B, SRSF2), and epigenetic regulators (e.g., TET2, ASXL1, DNMT3A), as well as specific cytogenetic abnormalities (e.g., 8 trisomies, 7 deletions/monosomies). Clinical studies exploring therapeutic options for higher-risk MDS/MPN overlap syndromes mostly involve hypomethylating agents, but other treatments such as lenalidomide and targeted agents such as JAK inhibitors and inhibitors targeting PARP, histone deacetylases, and the Ras pathway are under investigation. While these treatment modalities can provide partial disease control, allogeneic bone marrow transplantation (allo-BMT) is the only potentially curative option for patients. Important prognostic factors correlating with outcomes after allo-BMT include comorbidities, splenomegaly, karyotype alterations, and the bone marrow blasts percentage at the time of transplantation. Future research is imperative to optimizing therapeutic strategies and enhancing patient outcomes in MDS/MPN neoplasms. In this review, we summarize MDS/MPN diagnostic criteria, biology, and current and future treatment options, including bone marrow transplantation. Full article

(This article belongs to the Special Issue Recent Advances in the Understanding of Myelodysplastic Syndrome and Acute Myeloid Leukemia)

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16 pages, 21508 KiB

Open AccessReview

Secondary-Type Mutations in Acute Myeloid Leukemia: Updates from ELN 2022

by Ian M. Bouligny, Keri R. Maher and Steven Grant

Cancers 2023, 15(13), 3292; https://doi.org/10.3390/cancers15133292 - 22 Jun 2023

Cited by 2 | Viewed by 2812

Abstract

The characterization of the molecular landscape and the advent of targeted therapies have defined a new era in the prognostication and treatment of acute myeloid leukemia. Recent revisions in the European LeukemiaNet 2022 guidelines have refined the molecular, cytogenetic, and treatment-related boundaries between myelodysplastic neoplasms (MDS) and AML. This review details the molecular mechanisms and cellular pathways of myeloid maturation aberrancies contributing to dysplasia and leukemogenesis, focusing on recent molecular categories introduced in ELN 2022. We provide insights into novel and rational therapeutic combination strategies that exploit mechanisms of leukemogenesis, highlighting the underpinnings of splicing factors, the cohesin complex, and chromatin remodeling. Areas of interest for future research are summarized, and we emphasize approaches designed to advance existing treatment strategies. Full article

(This article belongs to the Special Issue Recent Advances in the Understanding of Myelodysplastic Syndrome and Acute Myeloid Leukemia)

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15 pages, 2250 KiB

Open AccessReview

How ITD Insertion Sites Orchestrate the Biology and Disease of FLT3-ITD-Mutated Acute Myeloid Leukemia

by Tobias R. Haage, Burkhart Schraven, Dimitrios Mougiakakos and Thomas Fischer

Cancers 2023, 15(11), 2991; https://doi.org/10.3390/cancers15112991 - 30 May 2023

Cited by 5 | Viewed by 3114

Abstract

Mutations of the FLT3 gene are among the most common genetic aberrations detected in AML and occur mainly as internal tandem duplications (FLT3-ITD). However, the specific sites of FLT3-ITD insertion within FLT3 show marked heterogeneity regarding both biological and clinical features. In contrast to the common assumption that ITD insertion sites (IS) are restricted to the juxtamembrane domain (JMD) of FLT3, 30% of FLT3-ITD mutations insert at the non-JMD level, thereby integrating into various segments of the tyrosine kinase subdomain 1 (TKD1). ITDs inserted within TKD1 have been shown to be associated with inferior complete remission rates as well as shorter relapse-free and overall survival. Furthermore, resistance to chemotherapy and tyrosine kinase inhibition (TKI) is linked to non-JMD IS. Although FLT3-ITD mutations in general are already recognized as a negative prognostic marker in currently used risk stratification guidelines, the even worse prognostic impact of non-JMD-inserting FLT3-ITD has not yet been particularly considered. Recently, the molecular and biological assessment of TKI resistance highlighted the pivotal role of activated WEE1 kinase in non-JMD-inserting ITDs. Overcoming therapy resistance in non-JMD FLT3-ITD-mutated AML may lead to more effective genotype- and patient-specific treatment approaches. Full article

(This article belongs to the Special Issue Recent Advances in the Understanding of Myelodysplastic Syndrome and Acute Myeloid Leukemia)

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25 pages, 2055 KiB

Open AccessReview

Progress toward Better Treatment of Therapy-Related AML

by Angeliki Kotsiafti, Konstantinos Giannakas, Panagiotis Christoforou and Konstantinos Liapis

Cancers 2023, 15(6), 1658; https://doi.org/10.3390/cancers15061658 - 8 Mar 2023

Cited by 1 | Viewed by 4270

Abstract

Therapy-related acute myeloid leukemia (t-AML) comprises 10–20% of all newly diagnosed cases of AML and is related to previous use of chemotherapy or ionizing radiotherapy for an unrelated malignant non-myeloid disorder or autoimmune disease. Classic examples include alkylating agents and topoisomerase II inhibitors, whereas newer targeted therapies such as poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitors have emerged as causative agents. Typically, t-AML is characterized by adverse karyotypic abnormalities and molecular lesions that confer a poor prognosis. Nevertheless, there are also cases of t-AML without poor-risk features. The management of these patients remains controversial. We describe the causes and pathophysiology of t-AML, putting emphasis on its mutational heterogeneity, and present recent advances in its treatment including CPX-351, hypomethylating agent plus venetoclax combination, and novel, molecularly targeted agents that promise to improve the cure rates. Evidence supporting personalized medicine for patients with t-AML is presented, as well as the authors’ clinical recommendations. Full article

(This article belongs to the Special Issue Recent Advances in the Understanding of Myelodysplastic Syndrome and Acute Myeloid Leukemia)

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