Transcriptome analysis of JAK2V617F HSPC and endogenous HSPC from irradiated and non-irradiated legs of recipient mice transplanted with JAK2V617F hematopoietic cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA698571 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:using transplantation of transgenic knock-in JAK2V617F hematopoietic cells into a single irradiated leg, we show development of Polycythemia Vera (PV) from a single anatomical site in immuno-competent mice. Mutant cells colonizing the non-irradiated leg efficiently induce PV. We compared transcriptomic profiles of sorted JAK2V617F HSPC and their reciprocal endogenous WT HSPC in the non-irradiated and irradiated legs from recipient mice transplanted with JAK2V617F hematopoietic cells.
2022-03-01 | GSE165902 | GEO
Project description:Loss-of-function mutations in EZH2 are associated with worse outcomes in patients with primary myelofibrosis (PMF). To understand how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for Ezh2 conditional deletion and a JAK2V617F transgene. The total bone marrow cells isolated from Cre-ERT2, Ezh2flox/flox;Cre-ERT2, JAK2V617F;Cre-ERT2 and JAK2V617F;Ezh2flox/flox;Cre-ERT2 mice were transplanted into lethally irradiated CD45.1+ wild-type recipient mice. As we deleted Ezh2 at four weeks post transplantation, we performed gene-expression analysis of LSKs and MEPs isolated from the recipient mice at 2 months post transplantation.
2015-06-04 | E-GEOD-69498 | biostudies-arrayexpress
Project description:In order to explore the gene expression signature in essential thrombocythemia (ET) patients in relation to JAK2V617F mutational status, expression profiling in circulating granulocytes was performed. Twenty ET were studied by microarray analysis and the results were confirmed by real-time quantitative RT-PCR in 40 ET patients, not receiving cytoreductive treatment. A heterogeneous molecular signature characterized by two main gene expression patterns was found: one with an up-regulation of inflammatory genes related to neutrophil activation and thrombosis, and the other one with significantly lower expression of these genes. Supervised clustering analysis showed 30 genes differentially expressed between JAK2V617F-negative and JAK2V617F-positive ET patients. Among the JAK2V617F-negative, a set of 14 genes (CISH, C13orf18, CCL3, PIM1, MAFF, SOCS3, ID2, GADD45B, KLF5, TNF, LAMB3, HRH4, TAGAP and TRIB1) showed an abnormal expression pattern. In this group of patients CISH, SOCS2, SOCS3 and PIM1 genes, all involved in JAK-STAT signaling pathway, presented a lower expression,. A two-gene predictor model was built comprising FOSB and CISH genes, which were the best discriminators of JAK2V617F status. In conclusion, JAK2V617F-negative ET patients present a characteristic gene expression profile, different from JAK2V617F-positive patients. Other pathways besides JAK-STAT might be implicated in the pathophysiology of JAK2V617F-negative ET patients. Keywords: Disease state analysis
2008-05-19 | GSE11003 | GEO
Project description:V617F driver mutation of JAK2 is the leading cause of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs). Loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes including erythrocytosis, neutrophilia, thrombocytosis, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality of JAK2V617F knockin mice. To reveal the role of Plek2 in the pathogenesis of JAK2V617F-induced MPNs and the detail mechanisms of its rescue, we performed RNA sequencing to analyze the gene expression profiles change between JAK2V617F/+ Plek2+/+ and JAK2V617F/+ Plek2-/- erythroblasts and hematopoietic stem/progenitor cells.
2019-04-11 | GSE97658 | GEO
Project description:Recent studies have shown that both TET2 mutation and JAK2V617F mutation are frequent in myeloproliferative neoplasms patients. The pathophysiological roles of each mutation have been elucidated in murine models, but the cooperative effect of the two mutations has not been elucidated yet. In this study, we examined the function of the cooperative effect of loss-of-TET2 function and JAK2V617F mutation in murine hematopoiesis. In this study, we utilized wild type (WT) mice, TET2 knock down (TET2KD) mice, JAK2V617F transgenic mice, double mutant mice. We transplanted 4 types of E14.5 fetal liver cells (WT, TET2KD, JAK2V617F, double mutant) into lethally irradiated mice. At 10-16 weeks post-transplantation, LSK cells from the BM of the recipients were collected, and gene expression analysis was performed. (WT,5 mice at 16 weeks; TET2KD, 5 mice at 10 weeks; JAK2V617F, 5 mice at 16 weeks; double mutant, 5 mice at 13 weeks)
2014-10-16 | E-GEOD-62302 | biostudies-arrayexpress
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:Loss-of-function mutations in EZH2 are associated with worse outcomes in patients with primary myelofibrosis (PMF). To understand how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for Ezh2 conditional deletion and a JAK2V617F transgene. The total bone marrow cells isolated from JAK2V617F;Ezh2flox/flox;Cre-ERT2 mice were transplanted into lethally irradiated CD45.1+ wild-type recipient mice. Post the deletion of Ezh2, we administered JAK2V617F/Ezh2?/? mice with JQ1 or control DMSO for two weeks, and performed gene-expression analysis of bone marrow LSKs and MEPs immediately after completion of JQ1 treatment.
2015-06-04 | E-GEOD-69499 | biostudies-arrayexpress
Project description:In order to explore the gene expression signature in essential thrombocythemia (ET) patients in relation to JAK2V617F mutational status, expression profiling in circulating granulocytes was performed. Twenty ET were studied by microarray analysis and the results were confirmed by real-time quantitative RT-PCR in 40 ET patients, not receiving cytoreductive treatment. A heterogeneous molecular signature characterized by two main gene expression patterns was found: one with an up-regulation of inflammatory genes related to neutrophil activation and thrombosis, and the other one with significantly lower expression of these genes. Supervised clustering analysis showed 30 genes differentially expressed between JAK2V617F-negative and JAK2V617F-positive ET patients. Among the JAK2V617F-negative, a set of 14 genes (CISH, C13orf18, CCL3, PIM1, MAFF, SOCS3, ID2, GADD45B, KLF5, TNF, LAMB3, HRH4, TAGAP and TRIB1) showed an abnormal expression pattern. In this group of patients CISH, SOCS2, SOCS3 and PIM1 genes, all involved in JAK-STAT signaling pathway, presented a lower expression,. A two-gene predictor model was built comprising FOSB and CISH genes, which were the best discriminators of JAK2V617F status. In conclusion, JAK2V617F-negative ET patients present a characteristic gene expression profile, different from JAK2V617F-positive patients. Other pathways besides JAK-STAT might be implicated in the pathophysiology of JAK2V617F-negative ET patients. Experiment Overall Design: Twenty ET were studied by microarray analysis and the results were confirmed by real-time quantitative RT-PCR in 40 ET patients. Microarray expression profiles were obtained using Whole Human Genome oligonucleotide microarrays (G4112A, Agilent Technologies, Palo Alto, CA). In each microarray experiment, RNA obtained from granulocytes from a single ET patient was compared with a pool of granulocyte RNAs from 10 healthy individuals. Duplicate hybridizations were performed for each comparison with dye-swapping to control.
2008-06-20 | E-GEOD-11003 | 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