RBM15 in leukemogenesis: an emerging regulator at the interface of RNA biology and hematopoiesis.

RNA-binding motif protein 15 (RBM15) is a key regulator of hematopoiesis and leukemogenesis, linking RNA metabolism, epitranscriptomic regulation, and lineage specification. Identified through the RBM15::MKL1 fusion in acute megakaryoblastic leukemia (AMKL), RBM15 functions within the N6-methyladenosine (m6A) writer complex, where its RNA-recognition motifs and Spen paralog and ortholog C-terminal domain enable site-specific methylation and protein recruitment. In hematopoietic stem and progenitor cells, RBM15 supports stem cell quiescence, self-renewal, and balanced lineage output, with additional roles in B cell, myeloid, and megakaryocytic differentiation. Mechanistically, RBM15 links m6A deposition to chromatin regulation, RNA export, and splicing. This review summarizes RBM15 structure, function, and regulation and highlights its emerging roles in leukemia, including AMKL and myelodysplastic syndromes, while outlining key questions for future studies.