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Mesenchymal Stromal Cell Senescence Induced by Dnmt3a-Mutant Haematopoietic Cells is a Targetable Mechanism Driving Clonal Haematopoiesis and Initiation of Leukemia

ABSTRACT: Clonal haematopoiesis (CH) is a benign age-related condition occurring due to somatic genetic variation in haematopoietic stem and progenitor cells (HSPCs). In some individuals, CH is a precursor condition for haematologic malignancy, but the mechanisms driving progression of CH to malignancy are incompletely understood. Given that malignant cells reprogram their microenvironment to create a self-reinforcing niche, we hypothesized that HSPCs carrying CH mutations have microenvironment-remodelling properties that promote their clonal advantage and contribute to malignant progression. By single-cell RNA-seq profiling of the non-haematopoietic bone marrow microenvironment in a mouse model of DNMT3A-mutant CH, we identified strong enrichment of a cellular senescence signature in bone marrow mesenchymal stromal cells (MSCs). We find that Dnmt3a-mutant HSPCs induce markers of senescence including SA-b-gal, BCL-2, BCL-xL, Cdkn1a (p21), and Cdkn2a (p16) selectively in MSCs using ex vivo and in vivo assays. This senescence induction phenotype is cell contact-independent and reproduced by IL-6 and TNFa, both of which are soluble factors produced by Dnmt3a-mutant HSPCs. Removal of senescent MSCs using Navitoclax reduced the selective growth advantage of Dnmt3a-mutant hematopoietic cells and reduced myeloproliferation in a Dnmt3a;Npm1-mutant model of myeloid neoplasms. Together, our data demonstrate that Dnmt3a-mutant HSPCs produce specific factors that reprogram their microenvironment through senescence induction, and that this process creates a self-reinforcing niche favouring their growth advantage and progression to malignancy.

ORGANISM(S): Mus musculus

PROVIDER: GSE240686 | GEO | 2025/04/15

REPOSITORIES: GEO

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Project description:Hematopoietic stem cells (HSCs) with certain somatic mutations, most commonly in the DNA methyltransferase DNMT3A, gain a clonal growth advantage leading to the development of clonal hematopoiesis (CH). The distinct functional differences that allow DNMT3A-mutant HSCs to gain a fitness advantage and outcompete wild-type HSC in the context of aging are not fully elucidated. We recently discovered that HSC aging is initiated by decline in local production of insulin-like growth factor 1 (IGF1). Here, we used a mouse model of DNMT3A-mutant CH (Dnmt3aR878H/+) to investigate the extent to which decline in IGF1 alters the selective advantage of Dnmt3aR878H/+ HSCs. Upon transplant into IGF1-deficient recipient mice, Dnmt3aR878H/+ HSCs gained enhanced selective advantage over wild-type HSCs and maintained lineage balanced blood production. As IGF1/mTOR signaling is well understood to regulate energy metabolism, we investigated underlying metabolic differences between Dnmt3aR878H/+ and wild-type HSCs. Dnmt3aR878H/+ HSPCs had similar glycolytic capacity as wild-type HSCs but enhanced mitochondrial reserve capacity and mitochondrial activation potential. To evaluate whether mitochondrial function is a targetable dependency of Dnmt3aR878H/+ HSCs, we administered the mitochondrial-targeted molecule MitoQ resulting in the depletion of their mitochondrial reserve capacity. We find that MitoQ reduces the competitive advantage of Dnmt3aR878H/+ hematopoiesis. To identify the mechanism(s) by which MitoQ alters Dnmt3aR878H/+ phenotypic expansion we evaluated transcriptional changes after MitoQ treatment and find altered response to Igf1/mTOR signaling compared to wild-type HSC. The altered response to Igf1/mTOR signaling in part mediates the Dnmt3aR878H/+ hematopoietic selective advantage. Taken together, our work supports that mitochondrial metabolic regulation is a key mechanism by which DNMT3A-mutant HSCs gain a selective advantage. Targeting this mechanism may maintain polyclonal hematopoiesis during aging and reduce the risk of CH-associated disease.

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Mesenchymal Stromal Cell Senescence Induced by Dnmt3a-Mutant Haematopoietic Cells is a Targetable Mechanism Driving Clonal Haematopoiesis and Initiation of Leukemia

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