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Biomedicines
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Molecular Mechanisms of Normal and Malignant Hematopoiesis
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Molecular Mechanisms of Normal and Malignant Hematopoiesis

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 11372

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 the bone marrow ensure lifelong hematopoietic homeostasis by giving rise to the full repertoire of blood cells via highly ordered differentiation processes, while maintaining a proper HSC pool via self-renewal. Recent technological advances including genome-wide profiling and chromatin analyses have provided overwhelming evidence that the genetic and epigenetic landscape in hematopoietic stem/progenitor cells changes dynamically during normal hematopoiesis and fate determination, which often becomes impaired under pathological conditions.

Highly heterogeneous genetic mutation profiles are commonly found in various hematopoietic malignancies, some of which can drive oncogenic transformation. In addition, epigenetic factors governing DNA (hydroxy)methylation, histone modifications, nucleosome remodeling, microRNAs, etc., act in concert with diverse transcription factors to tightly control the balance between HSC self-renewal, lineage specification, and differentiation. Chromatin modifiers are considered crucial factors that integrate inputs from the HSC microenvironment or intracellular metabolism with genetic programs to secure normal hematopoiesis. Thus, aberrant orchestration of genetic and epigenetic mechanisms that disrupts this balance has emerged as a key mechanism that can drive aberrant HSC maintenance and/or function, ultimately leading to various hematologic malignancies, including leukemias and lymphomas. Notably, the reversible nature of epigenetic aberrations makes epigenetic regulators a promising target for the effective treatment of hematologic disorders. Despite significant advances in our understanding of the impact of genetic and epigenetic disruptions on HSC biology and the pathophysiology of hematological malignancies, it still remains challenging to treat these diseases.

For this Special Issue, we invite reviews or original research articles that describe the roles of genetic or epigenetic factors in normal and malignant hematopoiesis. We will also accept articles addressing how hematopoietic cells consolidate inputs from the HSC niche or intracellular metabolism with genetic programs to secure normal HSC self-renewal and differentiation. Topics relevant to the discoveries of novel genetic and epigenetic perturbations, their functional contribution to hematological oncogenesis, and translational studies targeting these aberrations for treating hematological malignancies 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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • hematopoietic stem cells
  • self-renewal
  • differentiation
  • hematological malignancies
  • molecular mechanisms
  • genetic factors
  • epigenetic factors
  • transcriptional regulation
  • HSC niche
  • targeted therapy

Published Papers (5 papers)

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Research

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10 pages, 1318 KiB  
Article
Two-Time Multiplexed Targeted Next-Generation Sequencing Might Help the Implementation of Germline Screening Tools for Myelodysplastic Syndromes/Hematologic Neoplasms
by Oriol Calvete, Julia Mestre, Ruth M. Risueño, Ana Manzanares, Pamela Acha, Blanca Xicoy and Francesc Solé
Biomedicines 2023, 11(12), 3222; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11123222 - 05 Dec 2023
Viewed by 791
Abstract
Next-generation sequencing (NGS) tools have importantly helped the classification of myelodysplastic syndromes (MDS), guiding the management of patients. However, new concerns are under debate regarding their implementation in routine clinical practice for the identification of germline predisposition. Cost-effective targeted NGS tools would improve [...] Read more.
Next-generation sequencing (NGS) tools have importantly helped the classification of myelodysplastic syndromes (MDS), guiding the management of patients. However, new concerns are under debate regarding their implementation in routine clinical practice for the identification of germline predisposition. Cost-effective targeted NGS tools would improve the current standardized studies and genetic counseling. Here, we present our experience in a preliminary study detecting variants using a two-time multiplexed library strategy. Samples from different MDS patients were first mixed before library preparation and later multiplexed for a sequencing run. Two different mixes including a pool of three (3×) and four (4×) samples were evaluated. The filtered variants found in the individually sequenced samples were compared with the variants found in the two-time multiplexed studies to determine the detection efficiency scores. The same candidate variants were found in the two-time multiplexed studies in comparison with the individual tNGS. The variant allele frequency (VAF) values of the candidate variants were also compared. No significant differences were found between the expected and observed VAF percentages in both the 3× (p-value 0.74) and 4× (p-value 0.34) multiplexed studies. Our preliminary results suggest that the two-time multiplexing strategy might have the potential to help reduce the cost of evaluating germline predisposition. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Normal and Malignant Hematopoiesis)
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13 pages, 5670 KiB  
Article
High-Altitude Hypoxia Induces Excessive Erythrocytosis in Mice via Upregulation of the Intestinal HIF2a/Iron-Metabolism Pathway
by Sisi Zhou, Jun Yan, Kang Song and Ri-Li Ge
Biomedicines 2023, 11(11), 2992; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11112992 - 07 Nov 2023
Viewed by 836
Abstract
Excessive erythrocytosis (EE) is a preclinical form of chronic mountain sickness (CMS). The dysregulation of iron metabolism in high-altitude hypoxia may induce EE. The intestinal hypoxia-inducible factor 2 alpha (HIF2a) regulates the genes involved in iron metabolism. Considering these findings, we [...] Read more.
Excessive erythrocytosis (EE) is a preclinical form of chronic mountain sickness (CMS). The dysregulation of iron metabolism in high-altitude hypoxia may induce EE. The intestinal hypoxia-inducible factor 2 alpha (HIF2a) regulates the genes involved in iron metabolism. Considering these findings, we aimed to investigate the function and mechanism of intestinal HIF2α and the iron metabolism pathway in high-altitude EE mice. C57BL/6J mice were randomized into four groups: the low-altitude group, the high-altitude group, the high-altitude + HIF2α inhibitor group, and the high-altitude + vehicle group. In-vitro experiments were performed using the human intestinal cell line HCT116 cultured under hypoxic conditions for 24 h. Results showed that high-altitude hypoxia significantly increased the expression of intestinal HIF2α and iron metabolism-related genes, including Dmt1, Dcytb, Fpn, Tfrc, and Fth in EE mice. Genetic blockade of the intestinal HIF2α-iron metabolism pathway decreased iron availability in HCT116 cells during hypoxia. The HIF2α inhibitor PT2385 suppressed intestinal HIF2α expression, decreased iron hypermetabolism, and reduced excessive erythrocytosis in mice. These data support the hypothesis that exposure to high-altitude hypoxia can lead to iron hypermetabolism by activating intestinal HIF2α transcriptional regulation, and reduced iron availability improves EE by inhibiting intestinal HIF2α signaling. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Normal and Malignant Hematopoiesis)
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18 pages, 6603 KiB  
Article
Selective Inhibition of HDAC Class I Sensitizes Leukemia and Neuroblastoma Cells to Anticancer Drugs
by Elmira Vagapova, Maxim Kozlov, Timofey Lebedev, Karina Ivanenko, Olga Leonova, Vladimir Popenko, Pavel Spirin, Sergey Kochetkov and Vladimir Prassolov
Biomedicines 2021, 9(12), 1846; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9121846 - 06 Dec 2021
Cited by 9 | Viewed by 3457
Abstract
The acquired resistance of neuroblastoma (NB) and leukemia cells to anticancer therapy remains the major challenge in the treatment of patients with these diseases. Although targeted therapy, such as receptor tyrosine kinase (RTK) inhibitors, has been introduced into clinical practice, its efficacy is [...] Read more.
The acquired resistance of neuroblastoma (NB) and leukemia cells to anticancer therapy remains the major challenge in the treatment of patients with these diseases. Although targeted therapy, such as receptor tyrosine kinase (RTK) inhibitors, has been introduced into clinical practice, its efficacy is limited to patients harboring mutant kinases. Through the analysis of transcriptomic data of 701 leukemia and NB patient samples and cell lines, we revealed that the expression of RTK, such as KIT, FLT3, AXL, FGFR3, and NTRK1, is linked with HDAC class I. Although HDAC inhibitors have antitumor activity, they also have high whole-body toxicity. We developed a novel belinostat derivative named hydrazostat, which targets HDAC class I with limited off-target effects. We compared the toxicity of these drugs within the panel of leukemia and NB cell lines. Next, we revealed that HDAC inhibition with hydrazostat reactivates NTRK1, FGFR3, ROR2, KIT, and FLT3 expression. Based on this finding, we tested the efficacy of hydrazostat in combination with RTK inhibitor imatinib. Additionally, we show the ability of hydrazostat to enhance venetoclax-induced apoptosis. Thus, we reveal the connection between HDACs and RTK and describe a useful strategy to overcome the complications of single-agent therapies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Normal and Malignant Hematopoiesis)
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Review

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22 pages, 12995 KiB  
Review
Epigenetic Regulators of DNA Cytosine Modification: Promising Targets for Cancer Therapy
by Inkyung Jung, Jungeun An and Myunggon Ko
Biomedicines 2023, 11(3), 654; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11030654 - 21 Feb 2023
Cited by 3 | Viewed by 2011
Abstract
Epigenetic modifications are crucial regulators of gene expression that critically impact cell lineage differentiation, survival, and proliferation, and dysregulations are commonly observed in various cancers. The aberrantly modified epigenome confers unique features on tumor cells, including sustained proliferative potential, resistance to growth-suppressive or [...] Read more.
Epigenetic modifications are crucial regulators of gene expression that critically impact cell lineage differentiation, survival, and proliferation, and dysregulations are commonly observed in various cancers. The aberrantly modified epigenome confers unique features on tumor cells, including sustained proliferative potential, resistance to growth-suppressive or cell death signals, augmented replicative immortality, invasion, and metastasis. As a result, epigenetic abnormalities exhibit significant impacts on all stages of oncogenesis from its onset to progression to metastasis. Among various epigenetic mechanisms in mammals, DNA cytosine methylation–demethylation is recurrently disrupted in cancers. Due to its inherent reversibility, targeting DNA methylation dynamics has gained tremendous attention as a promising therapeutic option that can ameliorate the effects of cancer-specific epigenetic abnormalities by restoring normal conditions. Various small molecules targeting DNA (de)methylation regulators have been developed as potential cancer therapeutics, some of which are approved for usage in clinics. Clinical trials of many other molecules are underway for both hematological malignancies and solid tumors. In this review, we discuss the DNA methylation/demethylation pathway as a promising target for therapeutic intervention in cancer and highlight the development of various epigenetic drugs targeting DNA-modifying enzymes such as DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Normal and Malignant Hematopoiesis)
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11 pages, 1245 KiB  
Review
Alternative Splicing in Myeloid Malignancies
by Carmelo Gurnari, Simona Pagliuca and Valeria Visconte
Biomedicines 2021, 9(12), 1844; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9121844 - 06 Dec 2021
Cited by 6 | Viewed by 3127
Abstract
Alternative RNA splicing (AS) is an essential physiologic function that diversifies the human proteome. AS also has a crucial role during cellular development. In fact, perturbations in RNA-splicing have been implicated in the development of several cancers, including myeloid malignancies. Splicing dysfunction can [...] Read more.
Alternative RNA splicing (AS) is an essential physiologic function that diversifies the human proteome. AS also has a crucial role during cellular development. In fact, perturbations in RNA-splicing have been implicated in the development of several cancers, including myeloid malignancies. Splicing dysfunction can be independent of genetic lesions or appear as a direct consequence of mutations in components of the RNA-splicing machinery, such as in the case of mutations occurring in splicing factor genes (i.e., SF3B1, SRSF2, U2AF1) and their regulators. In addition, cancer cells exhibit marked gene expression alterations, including different usage of AS isoforms, possibly causing tissue-specific effects and perturbations of downstream pathways. This review summarizes several modalities leading to splicing diversity in myeloid malignancies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Normal and Malignant Hematopoiesis)
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