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Experimental Hematology Mar 2020Clonal hematopoiesis is a common premalignant condition defined by the abnormal expansion of clonally derived hematopoietic stem cells carrying somatic mutations in... (Review)
Review
Clonal hematopoiesis is a common premalignant condition defined by the abnormal expansion of clonally derived hematopoietic stem cells carrying somatic mutations in leukemia-associated genes. Apart from increasing age, this phenomenon occurs with higher frequency in individuals with lymphoid or solid tumors and is associated with exposures to genotoxic stress. Clonal hematopoiesis in this context confers a greater risk for developing therapy-related myeloid neoplasms and appears to contribute to adverse cancer-related survival through a variety of potential mechanisms. These include alterations of the bone marrow microenvironment, inflammatory changes in clonal effector cells and modulation of immune responses. Understanding how clonal hematopoiesis drives therapy-related myeloid neoplasm initiation and interactions with non-myeloid malignancies will inform screening and surveillance approaches and suggest targeted therapies in this vulnerable population. Here, we examine the clinical implications of clonal hematopoiesis in the cancer setting and discuss potential strategies to mitigate the adverse consequences of clonal expansion.
Topics: Clonal Evolution; DNA Damage; Hematologic Neoplasms; Hematopoiesis; Humans; Myeloproliferative Disorders
PubMed: 32044376
DOI: 10.1016/j.exphem.2020.02.001 -
Genes Apr 2022Polycythemia vera belongs to myeloproliferative neoplasms, essentially by affecting the erythroblastic lineage. JAK2 alterations have emerged as major driver mutations... (Review)
Review
Polycythemia vera belongs to myeloproliferative neoplasms, essentially by affecting the erythroblastic lineage. JAK2 alterations have emerged as major driver mutations triggering PV-phenotype with the mutation detected in nearly 98% of cases. That's why JAK2 targeting therapeutic strategies have rapidly emerged to counter the aggravation of the disease. Over decades of research, to go further in the understanding of the disease and its evolution, a wide panel of genetic alterations affecting multiple genes has been highlighted. These are mainly involved in alternative splicing, epigenetic, miRNA regulation, intracellular signaling, and transcription factors expression. If JAK2 mutation, irrespective of the nature of the alteration, is known to be a crucial event for the disease to initiate, additional mutations seem to be markers of progression and poor prognosis. These discoveries have helped to characterize the complex genomic landscape of PV, resulting in potentially new adapted therapeutic strategies for patients concerning all the genetic interferences.
Topics: Genetic Background; Humans; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Phenotype; Polycythemia Vera
PubMed: 35456443
DOI: 10.3390/genes13040637 -
Oncotarget Apr 2013
Topics: Animals; Antineoplastic Agents; Humans; Interferon-alpha; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Neoplastic Stem Cells
PubMed: 23660238
DOI: 10.18632/oncotarget.986 -
Blood Mar 2017Myeloproliferative neoplasms (MPNs) arise in the hematopoietic stem cell (HSC) compartment as a result of the acquisition of somatic mutations in a single HSC that... (Review)
Review
Myeloproliferative neoplasms (MPNs) arise in the hematopoietic stem cell (HSC) compartment as a result of the acquisition of somatic mutations in a single HSC that provides a selective advantage to mutant HSC over normal HSC and promotes myeloid differentiation to engender a myeloproliferative phenotype. This population of somatically mutated HSC, which initiates and sustains MPNs, is termed MPN stem cells. In >95% of cases, mutations that drive the development of an MPN phenotype occur in a mutually exclusive manner in 1 of 3 genes: , , or The thrombopoietin receptor, MPL, is the key cytokine receptor in MPN development, and these mutations all activate MPL-JAK-STAT signaling in MPN stem cells. Despite common biological features, MPNs display diverse disease phenotypes as a result of both constitutional and acquired factors that influence MPN stem cells, and likely also as a result of heterogeneity in the HSC in which MPN-initiating mutations arise. As the MPN clone expands, it exerts cell-extrinsic effects on components of the bone marrow niche that can favor the survival and expansion of MPN stem cells over normal HSC, further sustaining and driving malignant hematopoiesis. Although developed as targeted therapies for MPNs, current JAK2 inhibitors do not preferentially target MPN stem cells, and as a result, rarely induce molecular remissions in MPN patients. As the understanding of the molecular mechanisms underlying the clonal dominance of MPN stem cells advances, this will help facilitate the development of therapies that preferentially target MPN stem cells over normal HSC.
Topics: Calreticulin; Hematologic Neoplasms; Hematopoietic Stem Cells; Humans; Janus Kinase 2; Myeloproliferative Disorders; Neoplastic Stem Cells; Receptors, Thrombopoietin
PubMed: 28159736
DOI: 10.1182/blood-2016-10-696005 -
Blood Aug 2021Cohesin is a multisubunit protein complex that forms a ring-like structure around DNA. It is essential for sister chromatid cohesion, chromatin organization,... (Review)
Review
Cohesin is a multisubunit protein complex that forms a ring-like structure around DNA. It is essential for sister chromatid cohesion, chromatin organization, transcriptional regulation, and DNA damage repair and plays a major role in dynamically shaping the genome architecture and maintaining DNA integrity. The core complex subunits STAG2, RAD21, SMC1, and SMC3, as well as its modulators PDS5A/B, WAPL, and NIPBL, have been found to be recurrently mutated in hematologic and solid malignancies. These mutations are found across the full spectrum of myeloid neoplasia, including pediatric Down syndrome-associated acute megakaryoblastic leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and de novo and secondary acute myeloid leukemias. The mechanisms by which cohesin mutations act as drivers of clonal expansion and disease progression are still poorly understood. Recent studies have described the impact of cohesin alterations on self-renewal and differentiation of hematopoietic stem and progenitor cells, which are associated with changes in chromatin and epigenetic state directing lineage commitment, as well as genomic integrity. Herein, we review the role of the cohesin complex in healthy and malignant hematopoiesis. We discuss clinical implications of cohesin mutations in myeloid malignancies and discuss opportunities for therapeutic targeting.
Topics: Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Hematologic Neoplasms; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid; Mutation; Myeloproliferative Disorders; Neoplasm Proteins; Cohesins
PubMed: 34157074
DOI: 10.1182/blood.2019004259 -
Blood Apr 2010Constitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2...
Constitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC(50)] = 281nM), and proliferation of JAK2V617F(+) Ba/F3 cells (IC(50) = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F(+) polycythemia vera patients (IC(50) = 67nM) versus healthy donors (IC(50) > 400nM). In a mouse model of JAK2V617F(+) MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs.
Topics: Amino Acid Substitution; Animals; Apoptosis; Blood Cell Count; Cell Proliferation; Cell Survival; Colony-Forming Units Assay; Cytokines; Disease Models, Animal; Drug Screening Assays, Antitumor; Hematopoietic Stem Cells; Humans; Janus Kinase 1; Janus Kinase 2; Janus Kinases; Mice; Myeloproliferative Disorders; Nitriles; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction; Spleen; Treatment Outcome
PubMed: 20130243
DOI: 10.1182/blood-2009-04-214957 -
Nature Communications Sep 2022Interleukin-1β (IL-1β) is a master regulator of inflammation. Increased activity of IL-1β has been implicated in various pathological conditions including...
Interleukin-1β (IL-1β) is a master regulator of inflammation. Increased activity of IL-1β has been implicated in various pathological conditions including myeloproliferative neoplasms (MPNs). Here we show that IL-1β serum levels and expression of IL-1 receptors on hematopoietic progenitors and stem cells correlate with JAK2-V617F mutant allele fraction in peripheral blood of patients with MPN. We show that the source of IL-1β overproduction in a mouse model of MPN are JAK2-V617F expressing hematopoietic cells. Knockout of IL-1β in hematopoietic cells of JAK2-V617F mice reduces inflammatory cytokines, prevents damage to nestin-positive niche cells and reduces megakaryopoiesis, resulting in decrease of myelofibrosis and osteosclerosis. Inhibition of IL-1β in JAK2-V617F mutant mice by anti-IL-1β antibody also reduces myelofibrosis and osteosclerosis and shows additive effects with ruxolitinib. These results suggest that inhibition of IL-1β with anti-IL-1β antibody alone or in combination with ruxolitinib could have beneficial effects on the clinical course in patients with myelofibrosis.
Topics: Animals; Interleukin-1beta; Janus Kinase 2; Mice; Mice, Knockout; Myeloproliferative Disorders; Neoplasms; Nitriles; Osteosclerosis; Primary Myelofibrosis; Pyrazoles; Pyrimidines
PubMed: 36100613
DOI: 10.1038/s41467-022-32927-4 -
Blood Cancer Journal Nov 2023SRSF2 mutations are found in association with JAK2V617F in myeloproliferative neoplasms (MPN), most frequently in myelofibrosis (MF). However, the contribution of SRSF2...
SRSF2 mutations are found in association with JAK2V617F in myeloproliferative neoplasms (MPN), most frequently in myelofibrosis (MF). However, the contribution of SRSF2 mutation in JAK2V617F-driven MPN remains elusive. To investigate the consequences of SRSF2 and JAK2 mutations in MPN, we generated Cre-inducible Srsf2Jak2 knock-in mice. We show that co-expression of Srsf2 mutant reduced red blood cell, neutrophil, and platelet counts, attenuated splenomegaly but did not induce bone marrow fibrosis in Jak2 mice. Furthermore, co-expression of Srsf2 diminished the competitiveness of Jak2 mutant hematopoietic stem/progenitor cells. We found that Srsf2 mutant reduced the TGF-β levels but increased the expression of S100A8 and S100A9 in Jak2 mice. Furthermore, enforced expression of S100A9 in Jak2 mice bone marrow significantly reduced the red blood cell, hemoglobin, and hematocrit levels. Overall, these data suggest that concurrent expression of Srsf2 and Jak2 mutants reduces erythropoiesis but does not promote the development of bone marrow fibrosis in mice.
Topics: Animals; Mice; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Neoplasms; Polycythemia; Primary Myelofibrosis; Serine-Arginine Splicing Factors
PubMed: 38012156
DOI: 10.1038/s41408-023-00947-y -
Hematology/oncology Clinics of North... Oct 2012Myeloproliferative neoplasm (MPN) animal models accurately re-capitulate human disease in mice and have been an important tool for the study of MPN biology and therapy.... (Review)
Review
Myeloproliferative neoplasm (MPN) animal models accurately re-capitulate human disease in mice and have been an important tool for the study of MPN biology and therapy. Transplantation of BCR-ABL transduced bone marrow into irradiated syngeneic mice established the field of MPN animal modeling. Genetically engineered MPN animal models have enabled detailed characterization of the effects of specific MPN-associated genetic abnormalities on hematopoietic stem and progenitor cells (HSPCs). Xenograft models have allowed the study of primary human MPN-propagating cells in vivo. JAK2V617F, the most common molecular abnormality in BCR-ABL negative MPN, has been extensively studied using retroviral, transgenic, knock-in and xenograft models.
Topics: Animals; Disease Models, Animal; Humans; Mice; Myeloproliferative Disorders
PubMed: 23009938
DOI: 10.1016/j.hoc.2012.07.007 -
Current Hematologic Malignancy Reports Oct 2017Myeloproliferative neoplasms (MPNs) are recognized for their debilitating symptom burdens. The purpose of this review is to understand the complexity of the MPN symptom... (Review)
Review
PURPOSE OF REVIEW
Myeloproliferative neoplasms (MPNs) are recognized for their debilitating symptom burdens. The purpose of this review is to understand the complexity of the MPN symptom burden and identify how validated MPN Patient Reported Outcome (PRO) tools may be integrated into clinical practice to assess the MPN symptom burden.
RECENT FINDINGS
Significant heterogeneity exists both within and between MPN subtypes. Surrogates of disease burden such as risk scores and MPN chronicity often fail to correlate with symptomatic burden. Validated MPN PROs allow for precise and rapid assessment of the MPN symptom burden in clinical and trial settings. Their growing use among investigators has resulted in improved understanding of how the MPN disease burden and overall patient experience is impacted by novel and traditional therapies. PRO tools are an integral part of National Comprehensive Cancer Center (NCCN) guidelines for MPN treatment and should be regularly employed in disease burden assessment.
Topics: Hematologic Neoplasms; Humans; Myeloproliferative Disorders; Practice Guidelines as Topic
PubMed: 28942516
DOI: 10.1007/s11899-017-0399-5