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Stem Cell Biology of Myeloid Neoplasms 2.0
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Stem Cell Biology of Myeloid Neoplasms 2.0

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 12747

Special Issue Editor

Dr. Theodoros Karantanos

E-Mail Website
Guest Editor
Hematologic Malignancies, Department of Oncology, Johns Hopkins University Hospital, Sidney Kimmel Cancer Center, Boston, MA, USA
Interests: myelodysplastic syndrome; myeloproliferative neoplasms; acute myeloid leukemia; stem cell biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue "Stem Cell Biology of Myeloid Neoplasms".

Chronic myeloid neoplasms are a group of diseases caused by clonal expansion of hematopoietic stem and progenitor cells carrying somatic mutations. They are characterized by failure of normal hematopoiesis and increased risk of acute leukemia. Unfortunately, despite the addition of numerous novel agents in the armamentarium of leukemia physicians, the survival of patients with high-risk chronic myeloid neoplasms remains poor. The progression and relapse of these neoplasms is associated with the presence of cancer stem cells, which are usually resistant to standard treatments. Our understanding of the genomic, proteomic and metabolomic alterations of these cells needs to be further improved to effectively target and eliminate them.

This Special Issue discusses the recent discoveries related to the biology of stem cells in chronic myeloid neoplasms and their interactions with microenvironment. It will also provide an overview of novel approaches to target them. This covers studies at the basic and translational level but also clinical trials that have targeted specific pathways in these cells in patients with chronic myeloid neoplasms.

Thus, this Special Issue reviews the current understanding of the biology of stem cells in chronic myeloid neoplasms and the introduction of novel targeted therapies at the basic, translational, and clinical level.

Dr. Theodoros Karantanos
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

  • myelodysplastic syndrome
  • myeloproliferative neoplasms
  • acute myeloid leukemia
  • stem cell biology

Published Papers (4 papers)

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Research

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15 pages, 3052 KiB  
Article
Epigenetic Silencing of PTEN and Epi-Transcriptional Silencing of MDM2 Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents
by Paul Lee, Rita Yim, Kai-Kei Miu, Sin-Hang Fung, Jason Jinyue Liao, Zhangting Wang, Jun Li, Yammy Yung, Hiu-Tung Chu, Pui-Kwan Yip, Emily Lee, Eric Tse, Yok-Lam Kwong and Harinder Gill
Int. J. Mol. Sci. 2022, 23(10), 5670; https://doi.org/10.3390/ijms23105670 - 18 May 2022
Cited by 2 | Viewed by 2114
Abstract
In myelodysplastic syndrome (MDS), resistance to hypomethylating agents (HMA) portends a poor prognosis, underscoring the importance of understanding the molecular mechanisms leading to HMA-resistance. In this study, P39 and Kasumi-1 cells and their azacitidine-resistant and decitabine-resistant sublines were evaluated comparatively with transcriptomic and [...] Read more.
In myelodysplastic syndrome (MDS), resistance to hypomethylating agents (HMA) portends a poor prognosis, underscoring the importance of understanding the molecular mechanisms leading to HMA-resistance. In this study, P39 and Kasumi-1 cells and their azacitidine-resistant and decitabine-resistant sublines were evaluated comparatively with transcriptomic and methylomic analyses. Expression profiling and genome-wide methylation microarray showed downregulation of PTEN associated with DNA hypermethylation in P39 cell lines resistant to azacitidine and decitabine. This pattern of PTEN dysregulation was also confirmed in a cohort of patients failing treatment with HMA. DNA hypomethylation of MDM2 was detected with downregulation of MDM2 in HMA resistant cell lines. Long-read sequencing revealed significant RNA hypomethylation of MDM2 resulting in alternative splicing and production of a truncated MDM2 transcript in azacitidine-resistant P39 cells. The expression of this MDM2 truncated transcript was also significantly increased in HMA-resistant patients compared with HMA-responsive patients. In conclusion, epigenetic and epi-transcriptomic dysregulation of PTEN and MDM2 were associated with resistance to hypomethylating agents. Full article
(This article belongs to the Special Issue Stem Cell Biology of Myeloid Neoplasms 2.0)
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Review

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18 pages, 793 KiB  
Review
Non-Coding RNAs Are Implicit in Chronic Myeloid Leukemia Therapy Resistance
by Alexander Rudich, Ramiro Garzon and Adrienne Dorrance
Int. J. Mol. Sci. 2022, 23(20), 12271; https://doi.org/10.3390/ijms232012271 - 14 Oct 2022
Cited by 4 | Viewed by 2037
Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm initiated by the presence of the fusion gene BCR::ABL1. The development of tyrosine kinase inhibitors (TKIs) highly specific to p210BCR-ABL1, the constitutively active tyrosine kinase encoded by BCR::ABL1, has [...] Read more.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm initiated by the presence of the fusion gene BCR::ABL1. The development of tyrosine kinase inhibitors (TKIs) highly specific to p210BCR-ABL1, the constitutively active tyrosine kinase encoded by BCR::ABL1, has greatly improved the prognosis for CML patients. Now, the survival rate of CML nearly parallels that of age matched controls. However, therapy resistance remains a persistent problem in the pursuit of a cure. TKI resistance can be attributed to both BCR::ABL1 dependent and independent mechanisms. Recently, the role of non-coding RNAs (ncRNAs) has been increasingly explored due to their frequent dysregulation in a variety of malignancies. Specifically, microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs) have been shown to contribute to the development and progression of therapy resistance in CML. Since each ncRNA exhibits multiple functions and is capable of controlling gene expression, they exert their effect on CML resistance through a diverse set of mechanisms and pathways. In most cases ncRNAs with tumor suppressing functions are silenced in CML, while those with oncogenic properties are overexpressed. Here, we discuss the relevance of many aberrantly expressed ncRNAs and their effect on therapy resistance in CML. Full article
(This article belongs to the Special Issue Stem Cell Biology of Myeloid Neoplasms 2.0)
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18 pages, 705 KiB  
Review
Extracellular Vesicles in Myeloid Neoplasms
by Christina Karantanou, Valentina René Minciacchi and Theodoros Karantanos
Int. J. Mol. Sci. 2022, 23(15), 8827; https://doi.org/10.3390/ijms23158827 - 8 Aug 2022
Cited by 2 | Viewed by 2728
Abstract
Myeloid neoplasms arise from malignant primitive cells, which exhibit growth advantage within the bone marrow microenvironment (BMM). The interaction between these malignant cells and BMM cells is critical for the progression of these diseases. Extracellular vesicles (EVs) are lipid bound vesicles secreted into [...] Read more.
Myeloid neoplasms arise from malignant primitive cells, which exhibit growth advantage within the bone marrow microenvironment (BMM). The interaction between these malignant cells and BMM cells is critical for the progression of these diseases. Extracellular vesicles (EVs) are lipid bound vesicles secreted into the extracellular space and involved in intercellular communication. Recent studies have described RNA and protein alterations in EVs isolated from myeloid neoplasm patients compared to healthy controls. The altered expression of various micro-RNAs is the best-described feature of EVs of these patients. Some of these micro-RNAs induce growth-related pathways such as AKT/mTOR and promote the acquisition of stem cell-like features by malignant cells. Another well-described characteristic of EVs in myeloid neoplasms is their ability to suppress healthy hematopoiesis either via direct effect on healthy CD34+ cells or via alteration of the differentiation of BMM cells. These results support a role of EVs in the pathogenesis of myeloid neoplasms. mainly through mediating the interaction between malignant and BMM cells, and warrant further study to better understand their biology. In this review, we describe the reported alterations of EV composition in myeloid neoplasms and the recent discoveries supporting their involvement in the development and progression of these diseases. Full article
(This article belongs to the Special Issue Stem Cell Biology of Myeloid Neoplasms 2.0)
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34 pages, 1780 KiB  
Review
Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome
by Paul Lee, Rita Yim, Yammy Yung, Hiu-Tung Chu, Pui-Kwan Yip and Harinder Gill
Int. J. Mol. Sci. 2021, 22(19), 10232; https://doi.org/10.3390/ijms221910232 - 23 Sep 2021
Cited by 18 | Viewed by 5192
Abstract
Myelodysplastic syndrome (MDS) is a heterogeneous, clonal hematological disorder characterized by ineffective hematopoiesis, cytopenia, morphologic dysplasia, and predisposition to acute myeloid leukemia (AML). Stem cell genomic instability, microenvironmental aberrations, and somatic mutations contribute to leukemic transformation. The hypomethylating agents (HMAs), azacitidine and decitabine [...] Read more.
Myelodysplastic syndrome (MDS) is a heterogeneous, clonal hematological disorder characterized by ineffective hematopoiesis, cytopenia, morphologic dysplasia, and predisposition to acute myeloid leukemia (AML). Stem cell genomic instability, microenvironmental aberrations, and somatic mutations contribute to leukemic transformation. The hypomethylating agents (HMAs), azacitidine and decitabine are the standard of care for patients with higher-risk MDS. Although these agents induce responses in up to 40–60% of patients, primary or secondary drug resistance is relatively common. To improve the treatment outcome, combinational therapies comprising HMA with targeted therapy or immunotherapy are being evaluated and are under continuous development. This review provides a comprehensive update of the molecular pathogenesis and immune-dysregulations involved in MDS, mechanisms of resistance to HMA, and strategies to overcome HMA resistance. Full article
(This article belongs to the Special Issue Stem Cell Biology of Myeloid Neoplasms 2.0)
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