Table of Contents

In this Outlook, Wu and Levine discuss a recent study in this issue of Genes & Development by Pawar et al. that expands on how the chromatin regulator PHF6 and a substrate receptor for an E3 ubiquitin ligase, PHIP, collaboratively suppress AML progression. The authors deliberate on the mechanistic and contextual nuances of losing PHF6 function in the development of leukemia and their implications for addressing ancestry-specific differences in cancer treatment.

In this review, Goldberg et al. describe the contextual dependencies of aneuploidy and its contribution to cell-intrinsic and cell-extrinsic phenotypes in cancer. They also discuss recent advances in detecting, modeling, and targeting aneuploidy, reflecting the field's efforts to leverage aneuploidy-induced vulnerabilities into effective strategies in cancer diagnosis and therapy.

In this study, Alegrio-Louro et al. used cryo-EM to structurally show that the invertebrate protein Dsup and the vertebrate protein HMGN interact with an active chromatin-bearing nucleosome through similar binding mechanisms. This work reinforces the biological significance of conserved, ancient nucleosome-binding motifs that underlie the evolution of protein–chromatin interactions.

In this study, Briggs et al. describe the antiviral roles of oligoadenylate synthetase (OAS) isoforms in the activation of the RNase L-mediated RNA decay pathway during West Nile virus infection. OAS isoforms perform distinct roles in RNase L activation, viral RNA aggregation, and condensate formation, which together antagonize viral RNA biology.

In this study, He et al. describe a role for SUMO2 in facilitating the proper 3′ end processing of histone precursor mRNAs. SUMO2 supports the integrity and function of histone locus bodies by stabilizing FLASH interactions and promoting U7 snRNP biogenesis, together modulating 3′ end cleavage and polyadenylation.

In this study, Sakhawala et al. describe a noncanonical miRNA biogenesis pathway in which a germline-enriched, functional family of miRNAs—derived from independent RNA polymerase III transcribed transcripts—is processed in a manner dependent on Dicer but not on Microprocessor or other miRNA processing factors. Such differently processed miRNAs were identified in C. elegans and human data sets, suggesting that these nonclassical, young, de novo miRNAs may be representative of the evolution of conserved miRNA genes.

In this study, Pawar et al. report that the chromatin-binding protein PHF6 serves as a transcriptional repressor and partners with PHIP to suppress stemness programs in acute myeloid leukemia. They show that the loss of PHF6 and PHIP thereby supports the progression of chronic myelomonocytic leukemia to acute myeloid leukemia and posit that disparate proteins that are found mutated in leukemia may function as unified complexes.

In this study, Turn et al. use a genome-wide CRISPR screen to identify regulators of adipogenesis, including those controlling adipogenic differentiation, lipid accumulation, and mitotic clonal expansion. While reinforcing the importance of protein abundance and stability in this process, they validate two key pathways—hypusination and neddylation—with distinct contributions to adipogenesis and lipogenesis, highlighting the value of this resource in advancing a deeper mechanistic understanding of adipose tissue development and function.