Mesenchymal Stromal Cell Senescence Induced byDnmt3a-Mutant Hematopoietic Cells is a Targetable Mechanism Driving Clonal Hematopoiesis and Initiation of Hematologic Malignancy

Abstract

AbstractClonal hematopoiesis (CH) can predispose to blood cancers due to enhanced fitness of mutant hematopoietic stem and progenitor cells (HSPCs), but the mechanisms driving this progression are not understood. We hypothesized that malignant progression is related to microenvironment-remodelling properties of CH-mutant HSPCs. Single-cell transcriptomic profiling of the bone marrow microenvironment inDnmt3aR878H/+mice revealed signatures of cellular senescence in mesenchymal stromal cells (MSCs).Dnmt3aR878H/+HSPCs caused MSCs to upregulate the senescence markers SA-β-gal, BCL-2, BCL-xL,Cdkn1a(p21) andCdkn2a(p16),ex vivoandin vivo. This effect was cell contact-independent and can be replicated by IL-6 or TNFα, which are produced byDnmt3aR878H/+HSPCs. Depletion of senescent MSCsin vivoreduced the fitness ofDnmt3aR878H/+hematopoietic cells and the progression of CH to myeloid neoplasms using a sequentially inducibleDnmt3a;Npm1-mutant model. Thus,Dnmt3a-mutant HSPCs reprogram their microenvironment via senescence induction, creating a self-reinforcing niche favoring fitness and malignant progression.Statement of SignificanceMesenchymal stromal cell senescence induced byDnmt3a-mutant hematopoietic stem and progenitor cells drives clonal hematopoiesis and initiation of hematologic malignancy.