ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression
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PROVIDER: PRJNA935389 | ENA |
REPOSITORIES: ENA
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Project description:Myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), are clonal disorders driven by mutations in hematopoietic stem cells (HSCs). JAK2V617F is the most recurrent driver mutation in MPN and results in the constitutive activation of the JAK-STAT pathway. ZRSR2-loss is reported to cause mis-splicing of U12-type introns in myelodysplastic syndromes (MDS). Loss of function mutations in ZRSR2 have been found in a JAK2V617F-driven MPNs and are associated with disease progression and poor prognosis. However, the functional contribution of ZRSR2-loss to the pathogenesis and disease progression of MPN remains unknown. Using CRISPR-Cas9, we generated concomitant ZRSR2-loss in a JAK2V617F-driven human cell line and mouse model of MPN. RNA-Seq data demonstrates that ZRSR2-loss causes aberrant splicing in both human and murine cells, with the affect being more subtle in the murine context. Gene expression analysis in murine HSCs indicates that Zrsr2-loss biases lineage differentiation priming to megakaryocytes. However, Zrsr2-loss did not alter the severity or phenotype of the MPN in Jak2V617F mice. These results indicate that Zrsr2 mutations have limited impact on disease progression of Jak2V617F -driven MPN in vivo. Consistent with this, we find that ZRSR2 mutations are more frequently identified in genetically complex MPN patients carrying other high molecular risk mutations. In total, our findings demonstrate that ZRSR2-loss causes subtle mis-splicing in JAK2V617F-driven MPN that is not sufficient to drive disease progression in the absence of other high-risk mutations.
2025-02-02 | GSE225394 | GEO
Project description:Myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), are clonal disorders driven by mutations in hematopoietic stem cells (HSCs). JAK2V617F is the most recurrent driver mutation in MPN and results in the constitutive activation of the JAK-STAT pathway. ZRSR2-loss is reported to cause mis-splicing of U12-type introns in myelodysplastic syndromes (MDS). Loss of function mutations in ZRSR2 have been found in a JAK2V617F-driven MPNs and are associated with disease progression and poor prognosis. However, the functional contribution of ZRSR2-loss to the pathogenesis and disease progression of MPN remains unknown. Using CRISPR-Cas9, we generated concomitant ZRSR2-loss in a JAK2V617F-driven human cell line and mouse model of MPN. RNA-Seq data demonstrates that ZRSR2-loss causes aberrant splicing in both human and murine cells, with the affect being more subtle in the murine context. Gene expression analysis in murine HSCs indicates that Zrsr2-loss biases lineage differentiation priming to megakaryocytes. However, Zrsr2-loss did not alter the severity or phenotype of the MPN in Jak2V617F mice. These results indicate that Zrsr2 mutations have limited impact on disease progression of Jak2V617F -driven MPN in vivo. Consistent with this, we find that ZRSR2 mutations are more frequently identified in genetically complex MPN patients carrying other high molecular risk mutations. In total, our findings demonstrate that ZRSR2-loss causes subtle mis-splicing in JAK2V617F-driven MPN that is not sufficient to drive disease progression in the absence of other high-risk mutations.
2025-02-02 | GSE225395 | GEO
Project description:ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression II.
| PRJNA935393 | ENA
Project description:ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression I.
| PRJNA935391 | ENA
Project description:We report a Jak2V617F knock-in mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a selective competitive advantage over wild type HSCs. In contrast, myeloid progenitor populations are expanded and skewed towards the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to JAK2V617F positive MPN. LKS cells were isolated from wild type (n=4) and JAK2V617F mutant mice (n=4). RNA was extracted using Qiagen RNeasy Micro Kit according to manufacturers instruction and amplified using NUGEN amplification kit. cDNA was fragmented and biotinylated before hybridization onto Affymetrix Mouse Expression Array 430 2.0.
2010-05-28 | E-GEOD-21842 | biostudies-arrayexpress
Project description:We report a Jak2V617F knock-in mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a selective competitive advantage over wild type HSCs. In contrast, myeloid progenitor populations are expanded and skewed towards the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to JAK2V617F positive MPN.
2010-05-15 | GSE21842 | GEO
Project description:Cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms. Their mechanisms are poorly understood. To investigate the role of microvesicles in these events, we performed a proteomic analysis of microvesicles derived from red blood cells from mice with a myeloproliferative neoplasms (Jak2V617F Flex/WT ;VE-cadherin-Cre) vs. littermate controls.
2020-02-17 | PXD014451 | Pride
Project description:Mutant JAK2V617F is found in majority of patients with myeloproliferative neoplasm. While heterozygous JAK2V617F induced an ET-like phenotype, JAK2V617F homozygosity drives an severe PV-like phenotype in knock-in mice. HSCs from mice with homozygous JAK2V617F expression show impaired self-renewal in transplants. To understand the molecular mechanisms involved this HSC functional defect, microarray was performed on isolated LT-HSCs from mice expressing wildtype, heterozygous and homozygous expression of mutant JAK2.
2018-08-06 | E-MTAB-6878 | biostudies-arrayexpress
Project description:Janus kinases (JAKs) mediate cytokine signaling, cell growth and hematopoietic differentiation. Gain-of-function mutations activating JAK2 signaling are seen in the majority of myeloproliferative neoplasm (MPN) patients, most commonly due to the JAK2V617F driver allele. While clinically-approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic JAK inhibitor therapy in most patients. This has been postulated to be due to incomplete dependence on constitutive JAK/STAT signaling, alternative signaling pathways, and/or the presence of cooperating disease alleles; however we hypothesize this is due to the inability of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a Dre-rox/Cre-lox dual orthogonal recombinase system. Deletion of oncogenic Jak2V617F abrogates the MPN disease phenotype, induces mutant-specific cell loss including in hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition. Furthermore, reversal of Jak2V617F in MPN cells with antecedent loss of Tet2 abrogates the MPN phenotype and inhibits mutant stem cell persistence suggesting cooperating epigenetic-modifying alleles do not alter dependence on mutant JAK/STAT signaling. Our results suggest that mutant-specific inhibition of JAK2V617F represents the best therapeutic approach for JAK2V617F-mutant MPN and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.
2022-05-25 | GSE203464 | GEO
Project description:The somatic JAK2V617F mutation is found in a majority of patients with myeloproliferative neoplasms (MPN). Chronic inflammation is often associated with MPN, but the role of inflammation in the pathogenesis of MPN remains elusive. Expression of interleukin-1 (IL-1), a key regulator of inflammation, is found elevated in MPN. Here, we show that increased IL-1β enhances myeloid cell expansion and promotes the development of bone marrow (BM) fibrosis in heterozygous Jak2V617F mouse model of MPN. Genetic deletion of IL-1 receptor 1 (IL-1R1) preferentially inhibited the expansion of Jak2 mutant hematopoietic stem/progenitor cells. Furthermore, IL-1R1 deletion or blockade with anti-IL-1R1 antibody significantly reduced leukocytosis and splenomegaly, and markedly inhibited BM fibrosis in homozygous Jak2V617F mutant mice. Collectively, our results suggest that IL-1 signaling plays an important role in progression to BM fibrosis in MPN, and targeting of IL-1R1 could be a useful strategy for the treatment of myelofibrosis.
2022-08-05 | GSE180339 | GEO