Aberrant RNA splicing and development of hematological malignancies

Abstract

Dysregulation of pre-mRNA splicing and transcription is a key step in gene expression control in patients with leukemia. Herein, we discuss the occurrence of frequent overlap of mutations affecting epigenetic regulation and pre-mRNA splicing in patients with leukemia, which together promote leukemogenesis through coordinated effects on the epigenome and pre-mRNA splicing. In particular, we have determined an important pathogenic role of cross-talk between altered epigenetic state and pre-mRNA splicing, provided functional evidence that mutations in pre-mRNA splicing factors drive leukemia development, and uncovered spliceosomal changes as a novel mediator of IDH2 mutant leukemogenesis. By isolating specific pre-mRNA splicing events that functionally contribute to IDH2/SRSF2 double-mutant leukemogenesis, we found that loss of the Integrator complex plays an important role in leukemia development. Our studies provided new evidence that defects in the Integrator complex remarkably affect several gene expression programs associated with hematopoietic differentiation and signaling pathways via transcriptional pause-release dysregulation, blockade of myeloid differentiation, and promotion of leukemogenesis in the Idh2 mutant background in vivo. Moreover, our results revealed important translational implications, given the substantial efforts to pharmacologically inhibit mutant IDH1/2 and splicing factors.