Oncostatin M is a Master Regulator of an Inflammatory Network inDnmt3a-Mutant Hematopoietic Stem Cells

Abstract

ABSTRACTAge-associated clonal hematopoiesis (CH) occurs due to somatic mutations accrued in hematopoietic stem cells (HSCs) that confer a selective advantage in the context of aging. The mechanisms by which CH-mutant HSCs gain this advantage with aging are not comprehensively understood. Using unbiased transcriptomic approaches, we identify Oncostatin M (OSM) signaling as a candidate contributor to aging-drivenDnmt3a-mutant CH. We find thatDnmt3a-mutant HSCs from young mice do not functionally respond to acute OSM stimulation with respect to proliferation, apoptosis, hematopoietic engraftment, or myeloid differentiation. However, youngDnmt3a-mutant HSCs transcriptionally upregulate an inflammatory cytokine network in response to acute OSM stimulation including genes encoding IL-6, IL-1β and TNFα. In addition, OSM-stimulatedDnmt3a-mutant HSCs upregulate the anti-inflammatory genesSocs3, Atf3andNr4a1, creating a negative feedback loop limiting sustained activation of the inflammatory network. In the context of an aged bone marrow (BM) microenvironment with chronically elevated levels of OSM,Dnmt3a-mutant HSCs upregulate pro-inflammatory genes but do not upregulateSocs3, Atf3andNr4a1. Together, our work suggests that chronic inflammation with aging exhausts the regulatory mechanisms in young CH-mutant HSCs that resolve inflammatory states, and that OSM is a master regulator of an inflammatory network that contributes to age-associated CH.