DNMT3A R882H Is Not Required for Disease Maintenance in Primary Human AML but Is Associated with Increased Leukemia Stem Cell Frequency.

Genetic mutations are being thoroughly mapped in human cancers, yet a fundamental question in cancer biology is whether such mutations are functionally required for cancer initiation, maintenance of established cancer, or both. In this study, we examine this question in the context of human acute myeloid leukemia (AML), in which DNMT3AR882 missense mutations often arise early, in preleukemic clonal hematopoiesis, and corrupt the DNA methylation landscape to initiate leukemia. We developed CRISPR-based methods to directly correct DNMT3AR882 mutations in leukemic cells obtained from patients. Surprisingly, DNMT3AR882 mutations were largely dispensable for disease maintenance. Replacing DNMT3AR882 mutants with wild-type DNMT3A did not impair the ability of AML cells to engraft in vivo and minimally altered DNA methylation. Taken together, DNMT3AR882 mutations are initially necessary for AML initiation but are largely dispensable for disease maintenance. The notion that initiating oncogenes differ from those that maintain cancer has important implications for cancer evolution and therapy. SIGNIFICANCE: Understanding which driver mutations are required for cancer initiation, maintenance, or both phases remains poorly understood. In this study, we uncover that highly prevalent preleukemic DNMT3A mutations are only required during disease initiation but become dispensable after leukemic transformation, uncovering the context-specific role of this driver mutation with important therapeutic implications. See related commentary by Zhou and Huang, p. 428.