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TET2 Deficiency Increases the Competitive Advantage of Hematopoietic Stem Cells through Upregulation of Thrombopoietin Receptor Signaling

ABSTRACT: Ten-Eleven Translocation-2 (TET2) mutations drive the expansion of mutant hematopoietic stem cells (HSCs) in clonal hematopoiesis (CH). However, the precise mechanisms by which TET2 mutations confer a competitive advantage to HSCs remain unclear. Here, through an epigenetic drug screen, we discovered that inhibition of disruptor of telomeric silencing 1-like (DOT1L), a H3K79 methyltransferase, selectively reduced the fitness of Tet2 knockout (Tet2KO) hematopoietic stem and progenitor cells (HSPCs). Mechanistically, we found that TET2 deficiency increased H3K79 dimethylation and expression of Mpl, which encodes the thrombopoietin receptor (TPO-R). Correspondingly, TET2 deficiency was associated with a higher proportion of primitive Mpl-expressing (Mpl+) cells in the HSC compartment. Importantly, inhibition of Mpl expression or the signaling downstream of TPO-R was sufficient to reduce the competitive advantage of murine and human TET2-deficient HSPCs. Our findings demonstrate a critical role for aberrant TPO-R signaling in TET2 mutation-driven CH and uncover potential therapeutic strategies against this condition.

ORGANISM(S): Mus musculus

PROVIDER: GSE264041 | GEO | 2025/02/11

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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TET2 Deficiency Increases the Competitive Advantage of Hematopoietic Stem Cells through Upregulation of Thrombopoietin Receptor Signaling

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