Cell origin–dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy

SanMiguel, Jennifer M., Eudy, Elizabeth, Loberg, Matthew A., Miles, Linde A., Stearns, Tim, Mistry, Jayna J., Rauh, Michael J., Levine, Ross L. and Trowbridge, Jennifer J. (2022) Cell origin–dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy. Blood Advances, 6 (12). pp. 3666-3677. ISSN 2473-9529

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Abstract

In adult acute myeloid leukemia (AML), the acquisition of driver somatic mutations 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 use mice with inducible mutant alleles common in human CH (DNMT3AR882; mouse Dnmt3aR878H) and AML (NPM1c; mouse Npm1cA). We find that Dnmt3aR878H/1 hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced cytokine expression and proinflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. Dnmt3aR878H/1 HSCs are the most potent cell type transformed by Npm1cA, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA, in cooperation with Dnmt3aR878H, acutely increased the accessibility of a distinct set of promoters in HSCs compared with MPP cells. These promoters were enriched for cell cycling, PI3K/AKT/mTOR signaling, stem cell signatures, and targets of transcription factors, including NFAT and the chromatin binding factor HMGB1, which have been implicated in human AML. These results demonstrate cooperativity between preexisting Dnmt3aR878H and Npm1cA at the chromatin level, where specific loci altered in accessibility by Npm1cA are dependent on cell context as well as Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention in the transformation from CH to AML.

Item Type:	Article
Uncontrolled Keywords:	hematology,das to be completed,2026 ,/dk/atira/pure/subjectarea/asjc/2700/2720
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:	https://www.scopus.com/pages/publication...
Depositing User:	LivePure Connector
Date Deposited:	10 Nov 2026 16:30
Last Modified:	10 Nov 2026 16:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/105049
DOI:	10.1182/bloodadvances.2022006968

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