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DUSP1 deletion is synthetic lethal to JAK2V617F induced MPN

ABSTRACT: Despite significant advances in developing selective JAK2 tyrosine kinase inhibitors (TKI), its clinical efficacy is not durable. Reactivation of compensatory MEK-ERK and PI3K survival pathways sustained by inflammatory cytokine signaling causes treatment failure. Here, we show that JAK2V617F and cytokine signaling converge to induce MAPK negative-regulator, DUSP1, which accelerates P53 turnover by blocking P38 mediated phosphorylation and stabilization. Deletion of Dusp1 increases P53 phosphorylation and stabilization that results in selective demise of Jak2V617F clones. However, inhibition of Dusp1 by a small molecule inhibitor (BCI) failed to impart Jak2V617F clonal selectivity due to pERK1/2 rebound caused by off-target inhibition of DUSP6. Ectopic expression of Dusp6 and BCI treatment restored clonal selectively and eradicated the Jak2V617F cells. Our study shows that inflammatory cytokines and JAK2V617F signaling converge to induce Dusp1, which downregulates P53 that results in a higher apoptotic threshold. These data provide evidence that selectively targeting of DUSP1 will impart a curative response in JAK2V617F-driven MPN

ORGANISM(S): Mus musculus

PROVIDER: GSE229318 | GEO | 2026/04/30

REPOSITORIES: GEO

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Project description:Somatic mutations that cause the clonal outgrowth of mutant hematopoietic stem cells (HSCs), known as clonal hematopoiesis (CH), decay myeloid heterogeneity, activate inflammation, and increase the risk of atherosclerosis. However, whether lifestyle alters myeloid cell diversity by either modulating CH clone expansion or the phenotypic programming of CH mutant cells, thereby impacting atherosclerosis, is unknown. Here, in humans and mice and across mutations in Jak2, Tet2, p53 and Dnmt3a, we demonstrate mutation-dependent responses to lifestyle in CH and show that mutant cells are uniquely and selectively sensitive to lifestyle exposures. Sleep and exercise restrict Jak2 and Tet2 CH and its atherogenic consequences by diminishing the clonal expansion of mutant HSCs and reprogramming mutant bone marrow (BM) HSCs and aortic macrophages, but not their neighboring wildtype (WT) counterparts, through divergent brain-body axes. In two large human datasets, moderate-to-vigorous physical associated with less non-DNMT3A CH. In atherogenic mice with Jak2 or Tet2 but not p53 or Dnmt3a CH, uninterrupted sleep or exercise curtails clone expansion. In Jak2 CH sleep and exercise do so by selectively reprogramming mutant, but not WT, BM HSCs towards anti-proliferative and metabolically healthy phenotypes by tempering BM macrophage-HSC IL-1β signaling. Sleep or exercise also lessens Jak2-, Tet2-, and p53-, but not Dnmt3a-, driven atherosclerosis, partly independent of BM clonal dynamics, by locally reprogramming mutant macrophages in atherosclerotic lesions. In Jak2 mutant, but not adjacent WT, aortic macrophages, uninterrupted sleep reduces cell death, selectively blunting CLEC4E-dependent inflammasome activation and IL-1β generation, consequently diminishing lesions. Exercise, meanwhile, activates PAC1+ neurons in the brain’s locus coeruleus (LC), raising peripheral norepinephrine (NE), and preserves the expression of NE’s adrenergic receptor (ADR) β2 in Jak2V617F, but not cohabitant WT, aortic macrophages. Exercise-mediated NE signaling from the brain’s LC to Jak2V617F aortic macrophages selectively represses their inflammatory programing and atherosclerosis. Together, our findings uncover gene-lifestyle coaction and establish that healthy lifestyles gene-specifically diminish CH and selectively reprogram mutant HSCs and macrophages to maintain myeloid heterogeneity and cardiovascular health.

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DUSP1 deletion is synthetic lethal to JAK2V617F induced MPN

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