Early Driver, Late Bystander: Stage-Specific Roles of DNMT3A R882 Mutations Unveiled in Human AML

In this issue, Köhnke, Karigane, and colleagues applied allele-specific CRISPR/Cas9 correction in human acute myeloid leukemia samples to dissect the stage-specific functions of DNA methyltransferase 3A (DNMT3A) arginine 882 (R882) mutations. They demonstrate that DNMT3A R882 mutations are required to sustain self-renewal and inflammatory programs in preleukemic cells but become largely dispensable once leukemia is established, while still influencing leukemia stem cell frequency, thereby providing a strong preclinical rationale to reconsider the therapeutic window for targeting DNMT3A-mutant clones early in leukemogenesis. See related article by Köhnke et al., p. 592.