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Selection Pressures in the Aged Microenvironment Drive Transformation of Dnmt3a-Mutant Hematopoietic Stem Cells to Myeloid Malignancy

ABSTRACT: Driver somatic mutations in adult acute myeloid leukemia (AML) are often preceded by a benign or premalignant state termed clonal hematopoiesis (CH) for which the greatest risk factor is aging. To risk-stratify aged individuals and develop therapies to prevent AML, we need to understand the variables that promote transformation from CH to AML. Using our orthogonally inducible Dnmt3aR878H;Npm1cA-mutant model of progression from CH to myeloid malignancy, we find that in young mice, Dnmt3a mutation buffers against myeloid differentiation, proliferation, acquisition of cooperating mutations and transformation induced by stress, inflammation, and the oncogenic Npm1 mutation. However, when Dnmt3a;Npm1-mutant hematopoietic stem cells (HSCs) are transplanted into naturally aged recipient mice, they gain myeloid-biased differentiation capacity and have an accelerated transformation to AML. These results support the hypothesis that alterations in the aged microenvironment drive risk of AML in individuals with CH and help to explain why this Dnmt3a mutation is exceedingly rare in pediatric leukemias.

ORGANISM(S): Mus musculus

PROVIDER: GSE180116 | GEO | 2021/07/15

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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Selection Pressures in the Aged Microenvironment Drive Transformation of Dnmt3a-Mutant Hematopoietic Stem Cells to Myeloid Malignancy

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