Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm
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ABSTRACT:
PROVIDER: PRJNA315946 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3233380.fastq.gz | Fastqsanger.gz | |||
| SRR3233378.fastq.gz | Fastqsanger.gz | |||
| SRR3233379.fastq.gz | Fastqsanger.gz |
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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: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
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:Myelofibrosis (MF) is the deadliest form of myeloproliferative neoplasm (MPN). Pim1 expression is significantly elevated in MPN/MF hematopoietic progenitors. So, we investigated the role of Pim1 in myelofibrosis. We show that genetic ablation of Pim1 blocked the development of myelofibrosis induced by Jak2V617F and MPLW515L. Pharmacologic inhibition of Pim1 with a second-generation Pim kinase inhibitor TP-3654 significantly reduced leukocytosis, splenomegaly and attenuated bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of MF. Combined treatment of TP-3654 and Ruxolitinib resulted in greater reduction of spleen size, normalization of blood leukocyte counts and abrogation of bone marrow fibrosis in murine models of MF. TP-3654 treatment also preferentially inhibited Jak2V617F mutant hematopoietic progenitors in mice. Our results suggest that Pim1 plays an important role in the pathogenesis of MF, and inhibition of Pim1 with TP-3654 might be useful for treatment of MF.
2022-07-01 | GSE183467 | GEO
Project description:HiJAKing the hematopoietic system: a low-frequency JAK2V617F clone drives myeloproliferative neoplasm pathology
| PRJNA1167631 | ENA
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: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:JAK2V617F is one of the most common mutations in clonal hematopoiesis of indeterminate potential (CHIP) and a major driver of myeloproliferative neoplasms (MPN). To determine the impact of the low frequency JAK2V617F clone on both the hematopoietic system and the bone marrow (BM) stroma, we developed a traceable murine JAK2V617F MPN model where the disease is induced in unconditioned bone marrow transplantation (BMT) recipients. Whole BMT was performed via a single tail vein injection of 5.0x106 cells into unconditioned C57BL/6 Ptprca CD45.1+ recipient mice using CD45.2+ donor cells carrying JAK2V617F isolated from a Poly I:C inducible MPN-like model. BMT resulted in a PV-like phenotype (elevated hematocrit and leukocytosis) with an average donor cell chimerism in peripheral blood of 2.74%. Eight months after BMT, RNA-seq analysis of whole BM sorted according to CD45.1/CD45.2 expression showed significant upregulation of early erythroblast- and myeloid cell-specific transcripts, as well as downregulation of lymphoid transcripts in donor-derived cells compared to controls. Surprisingly, recipient-derived cells also showed upregulation of myeloid- and erythroblast-related transcripts, indicating a skewing of the non-JAK2V617F carrying recipient hematopoietic system towards an MPN-like phenotype. In addition, RNA-seq analysis of the BM stroma from JAK2V617F BMT recipients 28-32 weeks post-BMT indicated significant loss of osteo-mesenchymal transcripts. Consistently, micro-CT imaging indicated loss of trabecular bone. Our model uncovers the impact of JAK2V617F donor cells on the host BM microenvironment and hematopoietic system, driving an MPN phenotype even with low donor cell chimerism within unconditioned recipients. The observation that BMT recipient’s hematopoietic cells, which do not carry JAK2V617F, acquire unique transcriptomic and phenotypic profiles suggests that the MPN clone not only impacts hematopoiesis-supporting stroma but profoundly influences unmutated cells, challenging our current understanding and therapeutic approaches to MPNs and other CHIP-associated diseases.
2025-08-20 | GSE278496 | GEO
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