Lung adenocarcinoma arising in individuals who have never smoked is understudied, represents a substantial global health burden, and is genomically distinct from smoking-associated disease. Zhao and colleagues have identified transcriptomic subtypes with prognostic value, including in stage I disease, supporting phenotypic state as an important determinant of outcome for lung adenocarcinoma in individuals who have never smoked. See related article by Zhao et al., p. 460.
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.
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