Micheliolide exerts effects in MPNs by inhibiting STAT3/5 activation via covalently binding to STAT3/5 proteins
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE212305 | GEO | 2022/09/02
REPOSITORIES: GEO
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Project description:Background: Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential (CHIP) face a significantly elevated risk of cardiovascular diseases (CVDs). Endothelial cells (ECs) carrying the JAK2V617F mutation have been detected in many MPN patients. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in MPN patients. Methods: We investigated the impact of endothelial JAK2V617F mutation on CVD development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. Results and Conclusions: Our investigations revealed that JAK2V617F mutant ECs promote CVDs by impairing endothelial function and undergoing endothelial-to-mesenchymal transition (EndMT). Importantly, we discovered that inhibiting the endothelial thrombopoietin receptor MPL suppressed JAK2V617F-induced EndMT and prevented cardiovascular dysfunction caused by mutant ECs. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function, rendering it a promising therapeutic target for preventing or ameliorating cardiovascular complications in patients with MPNs.
2024-05-02 | GSE266434 | GEO
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
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:The mutant JAK2v617F is a driver of myeloproliferative neoplasms(MPNs). Consequently, several JAK2 inhibitors are currently being studied in clinical trials. The most investigated JAK2 inhibitor, Ruxolitinib, provides significant and sustained improvements in spleen related and constitutional symptoms secondary to the disease and represents a milestone in the treatment of myelofibrosis. However, JAK2 inhibitors are non-curative and murine experiments have shown that JAK2 inhibitors don?t eradicate MPN stem cells. In the present study, we determined the effect of the specific JAK2V617F inhibitor LY2784544 on leukemic stem (CD34+) cells (LSCs) using the JAK2V617F-bearing erythroleukemia cell line HEL. The LY2784544 treatment caused a transient proliferation inhibition and apoptosis of HEL cells, but a recovery occurred within a week. Thereafter, the continuous exposure of HEL cells to LY2784544 induced the accumulation of CD34+ LSCs, and the CD34+ cell fraction increased from 8% to over 90% by week 9, which was accompanied by substantially increased clonogenic potentials. A whole-transcript expression analysis revealed a significantly enhanced expression of the stem cell factor KLF4 in LY2784544 treated HEL cells. Inhibiting KLF4 expression attenuated LY2784544-mediated accumulation of CD34+ LSCs. Moreover, we further identified that the telomerase inhibitor GRN163L abolished the LY2784544-mediated CD34+ cell enrichment. Our findings collectively suggest that JAK2 inhibitors may cause enrichment of LSCs and are therefore unlikely to cure MPN as a monotherapy. Moreover, simultaneously targeting JAk2V617F and KLF4 or telomerase may be a novel strategy for MPN treatment.
2019-12-07 | GSE141602 | GEO
Project description:Interferons (IFNs) are cytokines with potent anti-neoplastic properties and significant clinical activity in the treatment of myeloproliferative neoplasms (MPNs). The use of pegylated IFN for the treatment of MPNs has been of particular interest, with several clinical trials establishing clinical responses. Here we demonstrate that chromatin assembly factor 1 subunit B (CHAF1B) is overexpressed in MPN patients. Targeted silencing of CHAF1B enhances transcription of IFN-stimulated genes and promotes IFN-dependent anti-neoplastic effects against MPN patient-derived cells. Our findings suggest that targeting CHAF1B in combination with IFN therapy may offer an avenue for the development of effective combination therapies for the treatment of MPNs.
2023-05-15 | PXD037376 | Pride
Project description:Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia and primary myelofibrosis show an inherent tendency for transformation into leukemia (MPN-blast phase), which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, examined chromosomal abnormalities by high-resolution single-nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. Frequent genomic alterations were found in MPN after leukemic transformation with up to 3-fold more genomic changes per sample compared to samples in chronic phase (p<0.001). We identified commonly altered regions involved in disease progression including established targets (ETV6, TP53 and RUNX1), as well as new candidate genes on 7q, 16q, 19p and 21q. Moreover, trisomy 8 or amplification of 8q24 (MYC) was almost exclusively detected in JAK2V617F(-) cases with MPN-blast phase. Remarkably, copy-number neutral-loss of heterozygosity (CNN-LOH) on either 7q or 9p including homozygous JAK2V617F was related to decreased survival after leukemic transformation (p=0.01 and p=0.016, respectively). Our high density SNP-array analysis of MPN genomes in the chronic compared to leukemic stage identified novel target genes and provided prognostic insights associated with the evolution to leukemia. Keywords: SNP-chip To identify oncogenic lesions in MPD, we performed a genome-wide analysis of primary MPD samples using high-density SNP arrays (Affymetrix GeneChip).
2010-05-29 | E-GEOD-19647 | biostudies-arrayexpress
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: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: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. HSC-enriched population from WT (CD45.1) or Jak2VF knockin (CD45.2), after 4 weeks of interferon alpha or vehicle treatment. N=4 per condition
2013-03-09 | E-GEOD-44961 | biostudies-arrayexpress
Project description:Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET) In this dataset, we compare the gene expression data of patients JAK2V617F vs. CALR-mutated MPN patients.
2018-10-29 | GSE120362 | GEO