Mistry, J. J. | bioRxiv Science

bioRxiv2024

Mesenchymal Stromal Cell Senescence Induced by Dnmt3a-Mutant Hematopoietic Cells is a Targetable Mechanism Driving Clonal Hematopoiesis and Initiation of Hematologic Malignancy

Clonal 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 in Dnmt3aR878H/+ mice revealed signatures of cellular senescence in mesenchymal stromal cells (MSCs). Dnmt3aR878H/+ HSPCs caused MSCs to upregulate the senescence markers SA-{beta}-gal, BCL-2, BCL-xL, Cdkn1a (p21) and Cdkn2a (p16), ex vivo and in vivo. This effect was cell contact-independent and can be replicated by IL-6 or TNF, which are produced by Dnmt3aR878H/+ HSPCs. Depletion of senescent MSCs in vivo reduced the fitness of Dnmt3aR878H/+ hematopoietic cells and the progression of CH to myeloid neoplasms using a sequentially inducible Dnmt3a;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 by Dnmt3a-mutant hematopoietic stem and progenitor cells drives clonal hematopoiesis and initiation of hematologic malignancy.

cell biology↗

bioRxiv2022

Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness Versus Lineage Output in Dnmt3a-Mutant Clonal Hematopoiesis

Clonal hematopoiesis resulting from enhanced fitness of mutant hematopoietic stem cells (HSCs) associates with both favorable and unfavorable health outcomes related to the types of mature mutant blood cells produced, but how this lineage output is regulated is unclear. Using a mouse model of a clonal hematopoiesis-associated mutation, DNMT3AR882/+ (Dnmt3aR878H/+), we found that aging-induced TNF signaling promoted the selective advantage of mutant HSCs as well as stimulated mutant B lymphoid cell production. Genetic loss of TNF receptor TNFR1 impaired mutant HSC fitness without altering lineage output, while loss of TNFR2 reduced lymphoid cell production and favored myeloid cell production from mutant HSCs without altering overall fitness. These results support a model where clone size and mature blood lineage production can be independently controlled to harness potential beneficial aspects of clonal hematopoiesis. Statement of SignificanceThrough identification and dissection of TNF signaling as a key driver of murine Dnmt3a-mutant hematopoiesis, we report the discovery that clone size and production of specific mature blood cell types can be independently regulated.

cell biology↗