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Molecular Cooperativity of Dnmt3a and Npm1 Mutations in Transformation from Clonal Hematopoiesis to Myeloid Malignancy

ABSTRACT: Driver somatic mutations in adult acute myeloid leukemia (AML) may be preceded by a benign state termed clonal hematopoiesis (CH). To develop therapeutic strategies to prevent leukemia development from CH, it is important to understand the mechanisms by which CH-driving and AML-driving mutations cooperate. Here, we utilize mice with inducible mutant alleles common in CH (DNMT3AR882; mouse Dnmt3aR878H/+) and AML (NPM1c; mouse Npm1cA/+). We find that Dnmt3aR878H/+ hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced expression of cytokine and pro-inflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. These Dnmt3aR878H/+ HSCs are transformed by activation of Npm1cA/+, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA/+ acutely increased accessibility of a distinct set of promoters in cooperation with Dnmt3aR878H/+ than it did as a single mutation. These promoters were enriched for pro-inflammatory response signatures, p53 pathway, DNA repair and targets of transcription factors implicated in AML, including Hmgb1 and Pax4. These results suggest cooperativity between pre-existing Dnmt3a mutation and Npm1 mutation at the chromatin level, where specific loci altered in accessibility by the Npm1 mutation are dependent on Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention of the transformation from CH to AML.

ORGANISM(S): Mus musculus

PROVIDER: GSE193720 | GEO | 2022/01/21

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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Molecular Cooperativity of Dnmt3a and Npm1 Mutations in Transformation from Clonal Hematopoiesis to Myeloid Malignancy

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