Cell Origin–Dependent Cooperativity of Mutant Dnmt3a and Npm1 in Clonal Hematopoiesis and Myeloid Malignancy

• Published in: Blood advances 2022-06, Vol.6 (12), p.3666-3677
• Main Authors: SanMiguel, Jennifer M., Eudy, Elizabeth, Loberg, Matthew A., Miles, Linde A., Stearns, Tim, Mistry, Jayna J., Rauh, Michael J., Levine, Ross L., Trowbridge, Jennifer J.
• Format: Article
• Language: English
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2022006968

In adult acute myeloid leukemia (AML), 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/+ 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. Dnmt3aR878H/+ 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 accessibility of a distinct set of promoters in HSCs compared to 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 pre-existing 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 into transformation from CH to AML.