Aberrant DNA cytosine methylation is a critical contributor to compromised tissue regeneration and malignant transformation, particularly during aging. In this issue of Cancer Discovery, Huang and colleagues define a new class of disease-associated DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A) variants with decreased de novo DNA methylation activity due increased proteasomal degradation that are able to drive clonal expansion of hematopoietic stem cells.See related article by Huang et al., p. 220.