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Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms
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Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 18905

Special Issue Editors

Dr. Chung Hoow Kok

E-Mail Website
Guest Editor
Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
Interests: hematological malignancies; bioinformatics; biomarkers; artificial intelligence; targeted therapy; precision medicine
Dr. David T Yeung

E-Mail Website
Guest Editor
Discipline of Medicine, University of Adelaide, Adelaide, SA 5000, Australia
Interests: myeloid malignancies; prognosis; targeted therapies; biomarkers; next-generation sequencing
Dr. Devendra Hiwase

E-Mail
Guest Editor
Royal Adelaide Hospital, Adelaide, SA 5000, Australia
Interests: MDS; AML; t-MN; targeted therapies; molecular pathogenesis

Special Issue Information

Dear Colleagues, 

We are delighted to announce a call for submissions to a Special Issue of the International Journal of Molecular Sciences on the topic of Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms.

Novel targeted therapies represent a paradigm shift in the management of myeloid neoplasms and acute myeloid leukemia (AML). However, resistance to therapy and disease progression remains a significant clinical issue. To overcome this issue, understanding the mechanism of resistance and progression is required for targeted therapy and providing an opportunity for precision medicine.

Topics included but are not limited to the following:

  1. AML
    1. Recent development in molecular biomarkers predicting prognosis of AML
    2. Minimal residual disease in AML
    3. Targeted therapies – FLT3 inhibitors, IDH1/IDH2 inhibitors, Venetoclax
    4. Novel therapies in 2022 and beyond
    5. Frailty and molecular targeted therapies
  2. MDS
    1. Recent development in molecular pathogenesis of MDS
    2. Recent advances in management of lower risk MDS: Are we making difference?
    3. Recent advances in management of high risk MDS
    4. Mechanism of azacitidine and HMA resistance and novel therapies to overcome the resistance
    5. t-MN: role of genetic predisposition and environemntal factors

We encourage submission of both original research articles and topical reviews. Since our journal is focused on molecular sciences, and therefore, pure clinical research is not fitted with this Special Issue. 

Dr. Chung Hoow Kok
Dr. David T Yeung
Dr. Devendra Hiwase
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. 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

  • mutations
  • next-generation sequencing
  • machine learning
  • artificial intelligence
  • targeted therapy
  • molecular pathogenesis
  • bioinformatics
  • biomarkers
  • AML
  • myeloid neoplasms

Published Papers (7 papers)

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Editorial

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5 pages, 191 KiB  
Editorial
Special Issue “Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms”
by Chung Hoow Kok, David T. Yeung and Devendra K. Hiwase
Int. J. Mol. Sci. 2024, 25(4), 2056; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25042056 - 08 Feb 2024
Viewed by 694
Abstract
Myeloid neoplasms (MNs) constitute a diverse group of haematological malignancies that includes myelodysplastic neoplasms (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndrome, and acute myeloid leukaemia (AML) [...] Full article
(This article belongs to the Special Issue Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms)

Research

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14 pages, 9733 KiB  
Article
Solute Carrier Family 29A1 Mediates In Vitro Resistance to Azacitidine in Acute Myeloid Leukemia Cell Lines
by Monika M. Kutyna, Sophie Loone, Verity A. Saunders, Deborah L. White, Chung H. Kok and Devendra K. Hiwase
Int. J. Mol. Sci. 2023, 24(4), 3553; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043553 - 10 Feb 2023
Viewed by 1654
Abstract
Azacitidine (AZA) is commonly used hypomethylating agent for higher risk myelodysplastic syndromes and acute myeloid leukemia (AML). Although some patients achieve remission, eventually most patients fail AZA therapy. Comprehensive analysis of intracellular uptake and retention (IUR) of carbon-labeled AZA (14C-AZA), gene [...] Read more.
Azacitidine (AZA) is commonly used hypomethylating agent for higher risk myelodysplastic syndromes and acute myeloid leukemia (AML). Although some patients achieve remission, eventually most patients fail AZA therapy. Comprehensive analysis of intracellular uptake and retention (IUR) of carbon-labeled AZA (14C-AZA), gene expression, transporter pump activity with or without inhibitors, and cytotoxicity in naïve and resistant cell lines provided insight into the mechanism of AZA resistance. AML cell lines were exposed to increasing concentrations of AZA to create resistant clones. 14C-AZA IUR was significantly lower in MOLM-13- (1.65 ± 0.08 ng vs. 5.79 ± 0.18 ng; p < 0.0001) and SKM-1- (1.10 ± 0.08 vs. 5.08 ± 0.26 ng; p < 0.0001) resistant cells compared to respective parental cells. Importantly, 14C-AZA IUR progressively reduced with downregulation of SLC29A1 expression in MOLM-13- and SKM-1-resistant cells. Furthermore, nitrobenzyl mercaptopurine riboside, an SLC29A inhibitor, reduced 14C-AZA IUR in MOLM-13 (5.79 ± 0.18 vs. 2.07 ± 0.23, p < 0.0001) and SKM-1-naive cells (5.08 ± 2.59 vs. 1.39 ± 0.19, p = 0.0002) and reduced efficacy of AZA. As the expression of cellular efflux pumps such as ABCB1 and ABCG2 did not change in AZA-resistant cells, they are unlikely contribute to AZA resistance. Therefore, the current study provides a causal link between in vitro AZA resistance and downregulation of cellular influx transporter SLC29A1. Full article
(This article belongs to the Special Issue Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms)
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21 pages, 4268 KiB  
Article
Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition
by Marte Karen Brattås, Anette Lodvir Hemsing, Kristin Paulsen Rye, Kimberley Joanne Hatfield and Håkon Reikvam
Int. J. Mol. Sci. 2022, 23(23), 14706; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314706 - 25 Nov 2022
Viewed by 1303
Abstract
Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a dismal prognosis. The cytoplasmic spleen tyrosine kinase (SYK) is highly expressed by hematopoietic cells and has emerged as a potential therapeutic target. In this study, we evaluated the in vitro antileukemic effects [...] Read more.
Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a dismal prognosis. The cytoplasmic spleen tyrosine kinase (SYK) is highly expressed by hematopoietic cells and has emerged as a potential therapeutic target. In this study, we evaluated the in vitro antileukemic effects of five SYK inhibitors, fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021, in a consecutive AML patient cohort. All inhibitors demonstrated a concentration-dependent antiproliferative effect, although there was considerable heterogeneity among patients. For fostamatinib and TAK-659, the antiproliferative effects were significantly higher in FLT3 mutated patients compared to nonmutated patients. Fostamatinib, entospletinib, TAK-659, and RO9021 induced significant apoptosis in primary AML cells, although the proapoptotic effects of the SYK inhibitors were less pronounced than the antiproliferative effects. Finally, most of the SYK inhibitors caused a significant decrease in the release of cytokines and chemokines from primary AML cells, indicating a potent inhibitory effect on the release of these leukemic signaling molecules. We concluded that the SYK inhibitors had antileukemic effects in AML, although larger studies are strongly needed to identify which patient subsets will benefit most from such a treatment. Full article
(This article belongs to the Special Issue Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms)
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18 pages, 2857 KiB  
Article
Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia
by Katja Seipel, Yvo Brügger, Harpreet Mandhair, Ulrike Bacher and Thomas Pabst
Int. J. Mol. Sci. 2022, 23(20), 12587; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012587 - 20 Oct 2022
Cited by 3 | Viewed by 2426
Abstract
In October 2020, the FDA granted regular approval to venetoclax (ABT-199) in combination with hypomethylating agents for newly-diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or in patients with comorbidities precluding intensive chemotherapy. The treatment response to venetoclax combination treatment, [...] Read more.
In October 2020, the FDA granted regular approval to venetoclax (ABT-199) in combination with hypomethylating agents for newly-diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or in patients with comorbidities precluding intensive chemotherapy. The treatment response to venetoclax combination treatment, however, may be short-lived, and leukemia relapse is the major cause of treatment failure. Multiple studies have confirmed the upregulation of the anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family and the activation of intracellular signaling pathways associated with resistance to venetoclax. To improve treatment outcome, compounds targeting anti-apoptotic proteins and signaling pathways have been evaluated in combination with venetoclax. In this study, the BCL-XL inhibitor A1331852, MCL1-inhibitor S63845, dual PI3K-mTOR inhibitor bimiralisib (PQR309), BMI-1 inhibitor unesbulin (PTC596), MEK-inhibitor trametinib (GSK1120212), and STAT3 inhibitor C-188-9 were assessed as single agents and in combination with venetoclax, for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Enhanced cytotoxic effects were present in all combination treatments with venetoclax in AML cell lines and AML patient samples. Elevated in vitro efficacies were observed for the combination treatment of venetoclax with A1331852, S63845 and bimiralisib, with differing response markers for each combination. For the venetoclax and bimiralisib combination treatment, responders were enriched for IDH2 and FLT3 mutations, whereas non-responders were associated with PTPN11 mutations. The combination of PI3K/mTOR dual pathway inhibition with bimiralisib and BCL2 inhibition with venetoclax has emerged as a candidate treatment in IDH2- and FLT3-mutated AML. Full article
(This article belongs to the Special Issue Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms)
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Review

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25 pages, 1519 KiB  
Review
Understanding the Continuum between High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia
by Phaedon D. Zavras, Ilias Sinanidis, Panagiotis Tsakiroglou and Theodoros Karantanos
Int. J. Mol. Sci. 2023, 24(5), 5018; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24055018 - 06 Mar 2023
Cited by 6 | Viewed by 3781
Abstract
Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm characterized by bone marrow dysplasia, failure of hematopoiesis and variable risk of progression to acute myeloid leukemia (AML). Recent large-scale studies have demonstrated that distinct molecular abnormalities detected at earlier stages of MDS alter disease [...] Read more.
Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm characterized by bone marrow dysplasia, failure of hematopoiesis and variable risk of progression to acute myeloid leukemia (AML). Recent large-scale studies have demonstrated that distinct molecular abnormalities detected at earlier stages of MDS alter disease biology and predict progression to AML. Consistently, various studies analyzing these diseases at the single-cell level have identified specific patterns of progression strongly associated with genomic alterations. These pre-clinical results have solidified the conclusion that high-risk MDS and AML arising from MDS or AML with MDS-related changes (AML-MRC) represent a continuum of the same disease. AML-MRC is distinguished from de novo AML by the presence of certain chromosomal abnormalities, such as deletion of 5q, 7/7q, 20q and complex karyotype and somatic mutations, which are also present in MDS and carry crucial prognostic implications. Recent changes in the classification and prognostication of MDS and AML by the International Consensus Classification (ICC) and the World Health Organization (WHO) reflect these advances. Finally, a better understanding of the biology of high-risk MDS and the mechanisms of disease progression have led to the introduction of novel therapeutic approaches, such as the addition of venetoclax to hypomethylating agents and, more recently, triplet therapies and agents targeting specific mutations, including FLT3 and IDH1/2. In this review, we analyze the pre-clinical data supporting that high-risk MDS and AML-MRC share the same genetic abnormalities and represent a continuum, describe the recent changes in the classification of these neoplasms and summarize the advances in the management of patients with these neoplasms. Full article
(This article belongs to the Special Issue Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms)
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20 pages, 514 KiB  
Review
Targeting Measurable Residual Disease (MRD) in Acute Myeloid Leukemia (AML): Moving beyond Prognostication
by Ing S. Tiong and Sun Loo
Int. J. Mol. Sci. 2023, 24(5), 4790; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054790 - 01 Mar 2023
Cited by 6 | Viewed by 5741
Abstract
Measurable residual disease (MRD) assessment in acute myeloid leukemia (AML) has an established role in disease prognostication, particularly in guiding decisions for hematopoietic cell transplantation in first remission. Serial MRD assessment is now routinely recommended in the evaluation of treatment response and monitoring [...] Read more.
Measurable residual disease (MRD) assessment in acute myeloid leukemia (AML) has an established role in disease prognostication, particularly in guiding decisions for hematopoietic cell transplantation in first remission. Serial MRD assessment is now routinely recommended in the evaluation of treatment response and monitoring in AML by the European LeukemiaNet. The key question remains, however, if MRD in AML is clinically actionable or “does MRD merely portend fate”? With a series of new drug approvals since 2017, we now have more targeted and less toxic therapeutic options for the potential application of MRD-directed therapy. Recent approval of NPM1 MRD as a regulatory endpoint is also foreseen to drastically transform the clinical trial landscape such as biomarker-driven adaptive design. In this article, we will review (1) the emerging molecular MRD markers (such as non-DTA mutations, IDH1/2, and FLT3-ITD); (2) the impact of novel therapeutics on MRD endpoints; and (3) how MRD might be used as a predictive biomarker to guide therapy in AML beyond its prognostic role, which is the focus of two large collaborative trials: AMLM26 INTERCEPT (ACTRN12621000439842) and MyeloMATCH (NCT05564390). Full article
(This article belongs to the Special Issue Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms)
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20 pages, 4562 KiB  
Review
The Contribution of JAK2 46/1 Haplotype in the Predisposition to Myeloproliferative Neoplasms
by Jhemerson Paes, George A. V. Silva, Andréa M. Tarragô and Lucivana P. de Souza Mourão
Int. J. Mol. Sci. 2022, 23(20), 12582; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012582 - 20 Oct 2022
Cited by 3 | Viewed by 2330
Abstract
Haplotype 46/1 (GGCC) consists of a set of genetic variations distributed along chromosome 9p.24.1, which extend from the Janus Kinase 2 gene to Insulin like 4. Marked by four jointly inherited variants (rs3780367, rs10974944, rs12343867, and rs1159782), this haplotype has a strong [...] Read more.
Haplotype 46/1 (GGCC) consists of a set of genetic variations distributed along chromosome 9p.24.1, which extend from the Janus Kinase 2 gene to Insulin like 4. Marked by four jointly inherited variants (rs3780367, rs10974944, rs12343867, and rs1159782), this haplotype has a strong association with the development of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) because it precedes the acquisition of the JAK2V617F variant, a common genetic alteration in individuals with these hematological malignancies. It is also described as one of the factors that increases the risk of familial MPNs by more than five times, 46/1 is associated with events related to inflammatory dysregulation, splenomegaly, splanchnic vein thrombosis, Budd–Chiari syndrome, increases in RBC count, platelets, leukocytes, hematocrit, and hemoglobin, which are characteristic of MPNs, as well as other findings that are still being elucidated and which are of great interest for the etiopathological understanding of these hematological neoplasms. Considering these factors, the present review aims to describe the main findings and discussions involving the 46/1 haplotype, and highlights the molecular and immunological aspects and their relevance as a tool for clinical practice and investigation of familial cases. Full article
(This article belongs to the Special Issue Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms)
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