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Identification of potential of new therapeutic approaches for JAK2 V617F mutant patients

ABSTRACT: n patients with PMF, excessive secretion of inflammatory cytokines results in fibrotic changes in bone marrow and diminishes the quality of life of the affected patients due to systemic symptoms long-term ruxolitinib therapy may reverse or markedly delay BM fibrosis progression in advanced MF suggests kavasincha 2018

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Bethany Geary

LAB HEAD: Bethany Geary

PROVIDER: PXD027250 | Pride | 2023-05-18

REPOSITORIES: Pride

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			Action	DRS
	2018_05_03_bML1.wiff	Wiff
	2018_05_03_bML1.wiff.1._idx2	Wiff
	2018_05_03_bML1.wiff.scan	Wiff
	2018_05_03_bML10.wiff	Wiff
	2018_05_03_bML10.wiff.scan	Wiff

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Gene expression profiling of granulocytes from primary and secondary myelofibrosis

Project description:Primary myelofibrosis (PMF) together with polycythemia vera (PV) and essential thrombocythemia (ET) belongs to the classic Philadelphia-negative myeloproliferative neoplasms (MPNs). PV and ET can evolve to secondary myelofibrosis (SMF) giving rise to post-PV (PPV) and post-ET (PET) myelofibrosis (MF). PMF and SMF patients are currently managed in the same way and prediction of survival is based on the same prognostic models, even if it has been demonstrated that they can’t accurately distinguish different risk categories in SMF. In the last few years interest grew concerning the ability of gene expression profiling (GEP) to provide valuable prognostic information for clinical decision making. To construct a molecular signature that can predict survival according to gene expression we studied GEP of granulocytes from 114 MF patients, including 35 prefibrotic/early PMF (Pre-PMF), 37 overt PMF (Overt-PMF), 26 PET and 16 PPV, using microarray platform.

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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.

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Gene expression data from CD34+ BMMCs/PBMCs from MPN patients vs. healthy controls

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Project description:Targeted inhibitors of JAK2 (e.g. ruxolitinib) often provide symptomatic relief for myeloproliferative neoplasm (MPN) patients, but the malignant clone persists and remains susceptible to disease transformation. These observations suggest that targeting alternative dysregulated signaling pathways may provide therapeutic benefit. Previous studies identified NFκB pathway hyperactivation in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) that was insensitive to JAK2 inhibition. Here, we provide evidence that NFκB pathway inhibition via pevonedistat targets malignant cells in MPN patient samples as well as in syngeneic MPN and patient-derived xenograft mouse models that is non-redundant with ruxolitinib. Colony forming assays revealed preferential inhibition of MF colony growth compared to normal colony formation. In mass cytometry studies, pevonedistat blunted canonical TNF⍺ responses in MF and sAML patient CD34+ cells. Pevonedistat also inhibited hyperproduction of inflammatory cytokines more effectively than ruxolitinib. Upon pevonedistat treatment alone or in combination with ruxolitinib, MPN mouse models exhibited reduced disease burden and improved survival. These studies demonstrating efficacy of pevonedistat in MPN cells in vitro as well as in vivo provide a rationale for therapeutic inhibition of NFκB signaling for MF treatment. Based on these findings, a Phase I clinical trial combining pevonedistat with ruxolitinib has been initiated.

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Identification of potential new therapeutic approaches for JAK2 V617F mutant patients

Project description:Myelofibrosis is often associated with the myeloproliferative neoplasms and expression of oncogenic JAK2 mutants. Patients with myelofibrosis have diminished quality of life due to systemic symptoms arising from fibrotic changes in the bone marrow. The introduction of the JAK2 inhibitor, ruxolitinib, has been of benefit in the treatment of myelofibrosis patients however, it is not curative and there is still a requirement for new targeted therapies to eradicate the cells at the heart of myelofibrosis pathology. Repurposing drugs bypasses many of the hurdles present in drug development, such as toxicity and pharmacodynamic profiling. To this end we undertook a re-analysis of our pre-existing proteomic data sets to identify perturbed biochemical pathways and their associated drugs/inhibitors to potentially target the cells driving myelofibrosis. This approach identified CBL0137 as a candidate for targeting JAK2 mutant driven malignancies. We therefore assessed CBL0137 as a new agent to extinguish JAK2 mutant primitive cells and show its ability to preferentially target cells from MF patients compared to healthy control cells. Further we define its mechanistic action in primary haemopoietic progenitor cells and demonstrate its ability to reduce splenomegaly and reticulocyte number in a transgenic murine model of myeloproliferative neoplasms.

2022-08-11 | E-MTAB-11653 | biostudies-arrayexpress

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Project description:Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET) and seconday myelofibrosis (pPV-MF or pET-MF) In this dataset, we compare the gene expression data of bone marrow (BM) or peripheral blood (PB) mononuclear cells of CD34+ cells from JAK2V617F mutated patients vs. healthy donors

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High-intensity pulse magnetic field promotes Escherichia coli division by affecting glucose metabolism

Project description:The biological effects of magnetic field (MF) have been studied and applied in medicine over the past four decades. However, high-intensity pulse magnetic field (HI-PMF), which may exert stronger biological effects in a shorter time, is rarely studied. Herein, this study aims to investigate the biological effects of 2.5 T HI-PMF on Escherichia coli and the consequent physiological alterations. After being treated by HI-PMF, a notable increase in intracellular NADH/NAD+ ratio was observed, accompanied by an enhanced survival rate. Transcriptome analysis revealed significant changes in genes associated with glycolysis, TCA cycle and oxidative phosphorylation, suggesting that HI-PMF induces an increase in glucose metabolism. Interestingly, the decreased intracellular glucose concentration could alleviate the inhibition of cell division, which was identified as the reason for the increased survival rate after being treated by HI-PMF. Conversely, low intracellular glucose level led to cell death under HI-PMF. Therefore, the results suggest that HI-PMF treatment promotes cellular glucose metabolism and further influences cell survival depending on intracellular glucose concentrations.

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Ruxolitinib mediated paradox JAK2 hyperphosphorylation is due to the protection of activation loop phosphotyrosines from phosphatases

Project description:Ruxolinitib was approved by the FDA for the treatment of JAK2-V617F positive myelofibrosis. Unexpectedly, treatment of JAK2-V617F expressing cells with ruxolitinib causes paradoxical hyperphosphorylation of JAK2 at Tyr1007/1008 sites. The mechanism of ruxolitinib-induced JAK2 hyperphosphorylation is not well understood. A ruxolitinib-resistant JAK2 variant (V617F+L983F) and a JAK2-V617F kinase dead mutant (JAK2-V617F+K882R) did not show paradox hyperphosphorylation after ruxolitinib treatment indicating that ruxolitinib-mediated JAK2 hyperphosphorylation is mediated by a JAK2 intrinsic mechanism. Native immunocomplexes of JAK2-V617F with an antibody against pTyr1007/1008 could be blocked by the presence of ruxolitinib, although JAK2-V617F was hyperphosphorylated at these sites, suggesting that in the presence of ruxolitinib the JAK2 activation loop is buried within the kinase domain. This stabilization of the activation loop conformation results in the protection of pTyr1007/1008 sites from phosphatases. When JAK2 is in an inhibited conformationally restricted state, the phosphate group of Tyr1007 and Tyr1008 forms an intermolecular interaction with Arg975 and Lys999, respectively. Mutation of Arg975 and Lys999 to Ala reduced the phosphorylation at both Tyr1007/1008 residues, and importantly, ruxolitinib treatment did not lead to JAK2 hyperphosphorylation in these variants. Hyperphosphorylated JAK2 is hyperactive after ruxolitinib dissociation and activates STAT5 target genes PIM2, ID1, and MPL. Our results suggest a novel mode of kinase regulation by modulating kinase activity through conformational changes induced by ruxolitinib.

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