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RNA-seq data from VavCre;Jak2+/+; Cdk6+/+, VavCre;Jak2V617F; Cdk6+/+, VavCre;Jak2V617F; Cdk6-/-, VavCre; Jak2+/+; Cdk6-/- murine bone marrow LSK cells and VavCre; Jak2V617F; Cdk6+/+ Palbociclib treated murine bone marrow LSK cells

ABSTRACT: We describe a critical role for Cdk6 in JAK2V617F+ MPN evolution. The absence of Cdk6 ameliorates clinical symptoms and prolongs survival of JAK2V617F fl/+ vav-Cre mice. The Cdk6 protein interferes with three hallmarks of disease: besides regulating malignant stem cell quiescence, it promotes NFkB signaling and contributes to cytokine production while inhibiting apoptosis. The treatment with palbociclib did not mirror these effects, showing that the functions of Cdk6 in MPN pathogenesis are largely kinase-independent.

ORGANISM(S): Mus musculus

PROVIDER: GSE123401 | GEO | 2019/06/10

REPOSITORIES: GEO

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RNA-seq data from VavCre;Jak2+/+; Cdk6+/+, VavCre;Jak2V617F; Cdk6+/+, VavCre;Jak2V617F; Cdk6-/-, VavCre; Jak2+/+; Cdk6-/- murine bone marrow LSK cells and VavCre; Jak2V617F; Cdk6+/+ Palbociclib treated murine bone marrow LSK cells

Project description:RNA-seq data from VavCre;Jak2+/+; Cdk6+/+, VavCre;Jak2V617F; Cdk6+/+, VavCre;Jak2V617F; Cdk6-/-, VavCre; Jak2+/+; Cdk6-/- murine bone marrow LSK cells and VavCre; Jak2V617F; Cdk6+/+ Palbociclib treated murine bone marrow LSK cells

| PRJNA508629 | ENA

Inhibition of CDK6 using Palbociclib in combination with Ruxolitinib markedly improves myelofibrosis in murine models

Project description:Myelofibrosis (MF) is a deadly blood neoplasia that presents the worst prognosis among myeloproliferative neoplasms (MPN). Expression of CDK6 is significantly elevated in MPN/MF hematopoietic progenitor cells. In this study, we investigated the efficacy of CDK4/6 inhibitor Palbociclib alone or in combination with Ruxolitinib in Jak2V617F and MPLW515L murine models of MF. Treatment of Palbociclib alone significantly reduced leukocytosis, splenomegaly and inhibited bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of MF. Combined treatment of Palbociclib and Ruxolitinib resulted in normalization of peripheral blood leukocyte counts, marked reduction of spleen size and abrogation of bone marrow fibrosis in murine models of MF. Mechanistically, we show that Palbociclib treatment or depletion of CDK6 inhibits Aurora kinase, NF-κB and TGF-β signaling pathways in Jak2V617F mutant hematopoietic cells. Overall, our data suggest that Palbociclib in combination with Ruxolitinib may have therapeutic potential for treatment of MF.

2021-11-05 | GSE173814 | GEO

Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm

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

Depletion of Jak2V617F MPN-propagating stem cells by interferon-alpha in a murine model of polycythemia vera

Project description:Interferon alpha (IFNa) is an effective treatment for patients with myeloproliferative neoplasms (MPN). In addition to inducing hematological responses in most MPN patients, IFNa reduces the JAK2V617F allelic burden and can render the JAK2V617F mutant clone undetectable in some patients. The precise mechanism underlying these responses is incompletely understood and whether the molecular responses that are seen occur due to the effects of IFNa on JAK2V617F mutant stem cells is debated. Using a murine model of Jak2V617F MPN, we investigated the effects of IFNa on Jak2V617F MPN-propagating stem cells in vivo. We report that IFNa treatment induces hematological responses in the model and causes depletion of Jak2V617F MPN-propagating cells over time, impairing disease transplantation. We demonstrate that IFNa treatment induces cell-cycle activation of Jak2V617F mutant long-term hematopoietic stem cells (LT-HSC) and promotes a predetermined erythroid-lineage differentiation program. These findings provide insights into the differential effects of IFNa on Jak2V617F mutant and normal hematopoiesis and suggest that IFNa achieves molecular remissions in MPN patients through its effects on MPN stem cells. Furthermore, these results support combinatorial therapeutic approaches in MPN, by concurrently depleting dormant JAK2V617F MPN-propagating stem cells with IFNa and targeting the proliferating downstream progeny with JAK2-inhibitors or cytotoxic chemotherapy.

2013-03-09 | GSE44961 | GEO

Depletion of Jak2V617F MPN-propagating stem cells by interferon-alpha in a murine model of polycythemia vera

2013-03-09 | E-GEOD-44961 | biostudies-arrayexpress

Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasms

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

Bone marrow erythroblast arrays

Project description:JAK2V617F mutation is found in most patients with a myeloproliferative neoplasm (MPN), including polycythemia vera (PV), essential thrombocythemia (ET). We have demonstrated that heterozygous human JAK2V617F are associated with ET-like phenotypes while homozygosity for human JAK2V617F results in a striking phenotypic switch from an ET-like to PV-like phenotype. The resultant erythrocytosis is driven by increased numbers of erythroid progenitors and enhanced erythroblast proliferation. To establish the molecular mechanisms and pathways involved in the erythrocytosis, microarray was performed on bone marrow erythroblasts isolated from 8-10 weeks old homozygous, heterozygous mice and wildtype controls (3 mice for each genotype).

2014-03-26 | E-MTAB-2427 | biostudies-arrayexpress

Expression data from loss-of-TET2 and/or JAK2V617F mutant Lineage-c-Kit+Sca-1+ (LSK) bone marrow cells

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

Expression data from loss-of-TET2 and/or JAK2V617F mutant Lineage-c-Kit+Sca-1+ (LSK) bone marrow cells

2014-10-16 | GSE62302 | GEO

Gene expression analysis of Thy1+LSK bone marrow cells from Nol3+/+ and Nol3-/- MPN mice

Project description:Apoptosis Repressor with Caspase Recruitment Domain (ARC) was recently found to be highly expressed in solid tumors and in blast cells of patients with acute myeloid leukemia (AML). In this study, we assessed the functional and molecular consequences of loss of ARC on the hematopoietic system. We found, unexpectedly, that deletion of Nol3 (the gene that encodes ARC) in mice leads to development of a myeloproliferative neoplasm (MPN) resembling primary myelofibrosis (PMF). Nol3-/--induced MPN is transplantable into secondary recipient mice and is characterized by anemia, thrombocytopenia, extramedullary hematopoiesis, and bone marrow fibrosis. Despite an overall reduction in bone marrow cellularity Nol3-/- MPN mice have an expanded Thy1+LSK stem cell population with increased cell cycling, in addition to a myelomonocytic differentiation bias. Molecularly, the Nol3-/--induced phenotype is, at least in part, mediated by activation of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) and MYC. Nol3-/- MPN Thy1+LSK cells show significant molecular similarities with primary CD34+ cells isolated from patients with PMF. Furthermore, we found that Nol3 is deleted in patients with human myeloid malignancies and has decreased expression in a subset of patients with de novo AML. Our results reveal a novel role of Nol3 in normal hematopoiesis and in the pathogenesis of myeloid malignancies. To obtain insight into the molecular mechanism of the Nol3-/- -induced MPN, we performed gene expression profiling on Thy1+LSK bone marrow cells from Nol3+/+ and Nol3-/- MPN mice

2017-02-17 | GSE76121 | GEO

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