Issues

Nonmutational epigenetic reprogramming has emerged as a hallmark of cancer, responsible for the acquisition of oncogenic gene-expression programs independent of genetic mutations. Among such epigenetic mechanisms is posttranscriptional modulation of gene expression, by which particular transcripts undergo differential splicing, chemical modification, or other processes that affect downstream protein abundance. On p. 180, Vujovic, de Rooij et al. screen RNA-binding genes for their essentiality in acute myeloid leukemia (AML) stem cells (LSC), identifying ELAVL1 as a protein factor that promotes LSC-associated metabolic and differentiation patterns via altered splicing and transcript stabilization. Wu, Jin, et al., on p. 228 and In The Spotlight by Janin and Esteller on p. 176, observe that METTL3-mediated m⁶A modification of splicing factor transcripts leads to increased translation efficiency and subsequent global splicing dysregulation as a driver of chronic lymphocytic leukemia (CLL) in which no splicing mutations have occurred. Both studies highlight the targeting of key RNA-binding proteins as potential therapeutic vulnerabilities in hematologic malignancies. The cover illustration represents an abstract view of RNA-protein interactions, increasingly found to be a central regulatory step in oncogenesis. Cover image by Tetiana Vavryk.