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Molecular Mechanism of Leukemia 2.0
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Molecular Mechanism of Leukemia 2.0

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

Deadline for manuscript submissions: closed (30 October 2023) | Viewed by 4028

Special Issue Editor

Dr. Myunggon Ko

E-Mail Website
Guest Editor
Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
Interests: DNA methylation; TET proteins; hematopoietic stem cells; hematopoiesis; leukemia; cancer epigenetics; cancer therapy; drug screen; metabolic diseases; obesity; diabetes; biosensor; signaling and gene expression
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hematopoietic stem cells (HSCs) in bone marrow ensure lifelong hematopoietic homeostasis by differentiating along the highly ordered differentiation pathways to activate the full repertoire of blood cell functions. They also undergo self-renewal to maintain a proper pool of HSCs in bone marrow. A series of genetic and epigenetic abnormalities sometimes occur in HSPCs (hematopoietic stem and progenitors), some of which lead to a disruption of the normal self-renewal, differentiation, proliferation, or survival of HSPCs, ultimately driving the neoplastic transformation of certain hematopoietic cell populations and an accumulation of these abnormal (also called ‘leukemic’) cells in bone marrow and the periphery, while substantially suppressing normal hematopoiesis. Changes in cellular metabolism or altered intercellular interactions with non-hematopoietic cells within the bone marrow niche can also contribute to oncogenesis. Thus, understanding the fundamental molecular basis that governs normal hematopoiesis and leukemogenesis will facilitate the development of more rational and effective therapeutic interventions.

For this Special Issue, we invite original research articles or reviews that describe the molecular mechanisms of leukemia and their therapeutic applications. We will accept articles addressing how genetic or epigenetic factors modulate normal HSC self-renewal and differentiation and how their dysregulation affects the development of various types of leukemia. Furthermore, the consolidation of inputs from the HSC niche or intracellular metabolism with (epi)genetic programs to secure normal hematopoiesis and their implications on the pathogenesis of leukemia are also of great interest. Topics relevant to discoveries of novel genetic and epigenetic alterations, their impact on hematological oncogenesis, and advanced mechanism-based therapeutic strategies are also welcomed.

Dr. Myunggon Ko
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

  • epigenetics
  • chromatin modifiers
  • DNA (hydroxy)methylation
  • histone modification
  • hematopoietic
  • stem cells
  • self-renewal
  • differentiation
  • hematological malignancies
  • molecular mechanisms
  • epigenetic therapy

Related Special Issue

Published Papers (3 papers)

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Research

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18 pages, 3156 KiB  
Article
Development of Novel Epigenetic Anti-Cancer Therapy Targeting TET Proteins
by Hyejin Kim, Inkyung Jung, Chan Hyeong Lee, Jungeun An and Myunggon Ko
Int. J. Mol. Sci. 2023, 24(22), 16375; https://doi.org/10.3390/ijms242216375 - 15 Nov 2023
Viewed by 1227
Abstract
Epigenetic dysregulation, particularly alterations in DNA methylation and hydroxymethylation, plays a pivotal role in cancer initiation and progression. Ten-eleven translocation (TET) proteins catalyze the successive oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized methylcytosines in DNA, thereby serving as central modulators [...] Read more.
Epigenetic dysregulation, particularly alterations in DNA methylation and hydroxymethylation, plays a pivotal role in cancer initiation and progression. Ten-eleven translocation (TET) proteins catalyze the successive oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized methylcytosines in DNA, thereby serving as central modulators of DNA methylation–demethylation dynamics. TET loss of function is causally related to neoplastic transformation across various cell types while its genetic or pharmacological activation exhibits anti-cancer effects, making TET proteins promising targets for epigenetic cancer therapy. Here, we developed a robust cell-based screening system to identify novel TET activators and evaluated their potential as anti-cancer agents. Using a carefully curated library of 4533 compounds provided by the National Cancer Institute, Bethesda, MD, USA, we identified mitoxantrone as a potent TET agonist. Through rigorous validation employing various assays, including immunohistochemistry and dot blot studies, we demonstrated that mitoxantrone significantly elevated 5hmC levels. Notably, this elevation manifested only in wild-type (WT) but not TET-deficient mouse embryonic fibroblasts, primary bone marrow-derived macrophages, and leukemia cell lines. Furthermore, mitoxantrone-induced cell death in leukemia cell lines occurred in a TET-dependent manner, indicating the critical role of TET proteins in mediating its anti-cancer effects. Our findings highlight mitoxantrone’s potential to induce tumor cell death via a novel mechanism involving the restoration of TET activity, paving the way for targeted epigenetic therapies in cancer treatment. Full article
(This article belongs to the Special Issue Molecular Mechanism of Leukemia 2.0)
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17 pages, 2393 KiB  
Article
Deciphering Potential Molecular Signatures to Differentiate Acute Myeloid Leukemia (AML) with BCR::ABL1 from Chronic Myeloid Leukemia (CML) in Blast Crisis
by Lara Boucher, Nathalie Sorel, Christophe Desterke, Mélanie Chollet, Laura Rozalska, Maria Pilar Gallego Hernanz, Emilie Cayssials, Anna Raimbault, Annelise Bennaceur-Griscelli, Ali G. Turhan and Jean-Claude Chomel
Int. J. Mol. Sci. 2023, 24(20), 15441; https://doi.org/10.3390/ijms242015441 - 22 Oct 2023
Viewed by 1497
Abstract
Acute myeloid leukemia (AML) with BCR::ABL1 has recently been recognized as a distinct subtype in international classifications. Distinguishing it from myeloid blast crisis chronic myeloid leukemia (BC-CML) without evidence of a chronic phase (CP), remains challenging. We aimed to better characterize this entity [...] Read more.
Acute myeloid leukemia (AML) with BCR::ABL1 has recently been recognized as a distinct subtype in international classifications. Distinguishing it from myeloid blast crisis chronic myeloid leukemia (BC-CML) without evidence of a chronic phase (CP), remains challenging. We aimed to better characterize this entity by integrating clonal architecture analysis, mutational landscape assessment, and gene expression profiling. We analyzed a large retrospective cohort study including CML and AML patients. Two AML patients harboring a BCR::ABL1 fusion were included in the study. We identified BCR::ABL1 fusion as a primary event in one patient and a secondary one in the other. AML-specific variants were identified in both. Real-time RT-PCR experiments demonstrated that CD25 mRNA is overexpressed in advanced-phase CML compared to AML. Unsupervised principal component analysis showed that AML harboring a BCR::ABL1 fusion was clustered within AML. An AML vs. myeloid BC-CML differential expression signature was highlighted, and while ID4 (inhibitor of DNA binding 4) mRNA appears undetectable in most myeloid BC-CML samples, low levels are detected in AML samples. Therefore, CD25 and ID4 mRNA expression might differentiate AML with BCR::ABL1 from BC-CML and assign it to the AML group. A method for identifying this new WHO entity is then proposed. Finally, the hypothesis of AML with BCR::ABL1 arising from driver mutations on a BCR::ABL1 background behaving as a clonal hematopoiesis mutation is discussed. Validation of our data in larger cohorts and basic research are needed to better understand the molecular and cellular aspects of AML with a BCR::ABL1 entity. Full article
(This article belongs to the Special Issue Molecular Mechanism of Leukemia 2.0)
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Review

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23 pages, 1863 KiB  
Review
Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia
by Andrew Wu, Xiaohu Liu, Clark Fruhstorfer and Xiaoyan Jiang
Int. J. Mol. Sci. 2024, 25(6), 3307; https://doi.org/10.3390/ijms25063307 - 14 Mar 2024
Viewed by 916
Abstract
Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream [...] Read more.
Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream signaling molecules to promote cellular survival and inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activity by preventing ATP entry, are widely used as a successful therapeutic in CML treatment. However, disease relapses and the emergence of resistant clones have become a critical issue for CML therapeutics. Two main reasons behind the persisting obstacles to treatment are the acquired mutations in the ABL1 kinase domain and the presence of quiescent CML leukemia stem cells (LSCs) in the bone marrow, both of which can confer resistance to TKI therapy. In this article, we systemically review the structural and molecular properties of the critical domains of BCR::ABL1 and how understanding the essential role of BCR::ABL1 kinase activity has provided a solid foundation for the successful development of molecularly targeted therapy in CML. Comparison of responses and resistance to multiple BCR::ABL1 TKIs in clinical studies and current combination treatment strategies are also extensively discussed in this article. Full article
(This article belongs to the Special Issue Molecular Mechanism of Leukemia 2.0)
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