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Stem Cell Biology of Myeloid Neoplasms

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 (31 October 2020) | Viewed by 12386

Special Issue 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,

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

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Keywords

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

Published Papers (4 papers)

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Research

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11 pages, 1258 KiB  
Article
Molecular Basis and Clinical Application of Growth-Factor-Independent In Vitro Myeloid Colony Formation in Chronic Myelomonocytic Leukemia
by Klaus Geissler, Eva Jäger, Agnes Barna, Michael Gurbisz, Temeida Graf, Elmir Graf, Thomas Nösslinger, Michael Pfeilstöcker, Sigrid Machherndl-Spandl, Reinhard Stauder, Armin Zebisch, Heinz Sill, Leopold Öhler, Rajko Kusec, Gregor Hörmann and Peter Valent
Int. J. Mol. Sci. 2020, 21(17), 6057; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176057 - 22 Aug 2020
Cited by 3 | Viewed by 2047
Abstract
We have originally reported that colony-forming units granulocyte/macrophage (CFU-GM) formation is an in vitro feature of chronic myelomonocytic leukemia (CMML) and a strong predictor for short survival. Elucidation of the molecular basis underlying this in vitro phenomenon could be helpful to define molecular [...] Read more.
We have originally reported that colony-forming units granulocyte/macrophage (CFU-GM) formation is an in vitro feature of chronic myelomonocytic leukemia (CMML) and a strong predictor for short survival. Elucidation of the molecular basis underlying this in vitro phenomenon could be helpful to define molecular features that predict inferior outcome in patients. We studied the correlation between the mutational landscape and spontaneous colony formation in 164 samples from 125 CMML patients. As compared to wildtype samples, spontaneous in vitro CFU-GM formation was significantly increased in samples containing mutations in NRAS, CBL and EZH2 that were confirmed as independent stimulatory factors by multiple regression analysis. Inducible expression of mutated RAS but not JAK2 was able to induce growth factor independence of Ba/F3 cells. Whereas high colony CFU-GM growth was a strong unfavorable parameter for survival (p < 0.00001) and time to transformation (p = 0.01390), no single mutated gene had the power to significantly predict for both outcome parameters. A composite molecular parameter including NRAS/CBL/EZH2, however, was predictive for inferior survival (p = 0.00059) as well as for increased risk of transformation (p = 0.01429). In conclusion, we show that the composite molecular profile NRAS/CBL/EZH2 derived from its impact on spontaneous in vitro myeloid colony formation improves the predictive power over single molecular parameters in patients with CMML. Full article
(This article belongs to the Special Issue Stem Cell Biology of Myeloid Neoplasms)
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Review

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11 pages, 277 KiB  
Review
Sex-Related Differences in Chronic Myeloid Neoplasms: From the Clinical Observation to the Underlying Biology
by Theodoros Karantanos, Tania Jain, Alison R. Moliterno, Richard J. Jones and Amy E. DeZern
Int. J. Mol. Sci. 2021, 22(5), 2595; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052595 - 05 Mar 2021
Cited by 9 | Viewed by 2196
Abstract
Chronic myeloid neoplasms are clonal diseases with variable clinical course and outcomes and despite the introduction of novel therapies, patients with high-risk disease continue to have overall poor outcomes. Different groups have highlighted that men have overall worse survival and higher incidence of [...] Read more.
Chronic myeloid neoplasms are clonal diseases with variable clinical course and outcomes and despite the introduction of novel therapies, patients with high-risk disease continue to have overall poor outcomes. Different groups have highlighted that men have overall worse survival and higher incidence of transformation to acute leukemia compared to women across neoplasms such as myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap neoplasms, and CML. More recent studies evaluating the genomic profile of patients with these neoplasms demonstrated a male predominance for mutations in high-risk genes including ASXL1, U2AF1, SRSF2 and ZRSR2. The understanding of the underlying biology is limited but a number of hypotheses have been developed and are currently being investigated. This review summarizes the current knowledge about sex-related differences in the clinical outcomes and genomic profile of patients with chronic myeloid neoplasms and discusses the hypothesized biologic mechanisms as an attempt to explain these observations. Full article
(This article belongs to the Special Issue Stem Cell Biology of Myeloid Neoplasms)
39 pages, 1273 KiB  
Review
Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms
by Yammy Yung, Emily Lee, Hiu-Tung Chu, Pui-Kwan Yip and Harinder Gill
Int. J. Mol. Sci. 2021, 22(2), 659; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020659 - 11 Jan 2021
Cited by 9 | Viewed by 4240
Abstract
Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and [...] Read more.
Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment. Full article
(This article belongs to the Special Issue Stem Cell Biology of Myeloid Neoplasms)
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27 pages, 422 KiB  
Review
NPM1-Mutated Myeloid Neoplasms with <20% Blasts: A Really Distinct Clinico-Pathologic Entity?
by Fabio Forghieri, Vincenzo Nasillo, Ambra Paolini, Francesca Bettelli, Valeria Pioli, Davide Giusti, Andrea Gilioli, Corrado Colasante, Gloria Acquaviva, Giovanni Riva, Patrizia Barozzi, Rossana Maffei, Leonardo Potenza, Roberto Marasca, Claudio Fozza, Enrico Tagliafico, Tommaso Trenti, Patrizia Comoli, Giuseppe Longo and Mario Luppi
Int. J. Mol. Sci. 2020, 21(23), 8975; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238975 - 26 Nov 2020
Cited by 24 | Viewed by 3315
Abstract
Nucleophosmin (NPM1) gene mutations rarely occur in non-acute myeloid neoplasms (MNs) with <20% blasts. Among nearly 10,000 patients investigated so far, molecular analyses documented NPM1 mutations in around 2% of myelodysplastic syndrome (MDS) cases, mainly belonging to MDS with excess of [...] Read more.
Nucleophosmin (NPM1) gene mutations rarely occur in non-acute myeloid neoplasms (MNs) with <20% blasts. Among nearly 10,000 patients investigated so far, molecular analyses documented NPM1 mutations in around 2% of myelodysplastic syndrome (MDS) cases, mainly belonging to MDS with excess of blasts, and 3% of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) cases, prevalently classified as chronic myelomonocytic leukemia. These uncommon malignancies are associated with an aggressive clinical course, relatively rapid progression to overt acute myeloid leukemia (AML) and poor survival outcomes, raising controversies on their classification as distinct clinico-pathologic entities. Furthermore, fit patients with NPM1-mutated MNs with <20% blasts could benefit most from upfront intensive chemotherapy for AML rather than from moderate intensity MDS-directed therapies, although no firm conclusion can currently be drawn on best therapeutic approaches, due to the limited available data, obtained from small and mainly retrospective series. Caution is also suggested in definitely diagnosing NPM1-mutated MNs with blast count <20%, since NPM1-mutated AML cases frequently present dysplastic features and multilineage bone marrow cells showing abnormal cytoplasmic NPM1 protein delocalization by immunohistochemical staining, therefore belonging to NPM1-mutated clone regardless of blast morphology. Further prospective studies are warranted to definitely assess whether NPM1 mutations may become sufficient to diagnose AML, irrespective of blast percentage. Full article
(This article belongs to the Special Issue Stem Cell Biology of Myeloid Neoplasms)
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