RBM5 is essential for the maintenance of leukemia stem cells by regulating a leukemic transcription program in cooperation with MYC [bulk RNA-seq]

Acute myeloid leukemia (AML) represents a type of malignant hematological disease that is caused by the dysregulated developmental program of leukemia stem cells (LSCs). RBM5 was recently reported as a key regulator in maintaining the survival of human leukemia cells via non-canonical transcriptional activation of HOXA9. However, its function in LSCs and the broad genome-wide transcriptional targets remain elusive. Here, we report that RBM5 is required for murine leukemogenesis and maintains self-renewal of LSCs in vivo, but dispensable for normal hematopoiesis. RBM5 is highly expressed in LSCs, and its deficiency results in specifically defective LSC function with the inhibition of self-renewal gene expression and induction of myeloid differentiation program. Gene expression, chromatin accessibility, and direct genome-wide RBM5 binding further identify the direct transcriptional targets of RBM5 in primary leukemia cells including several stemness genes Hoxa9 and Myc. Forced expression of both HOXA9 and MYC rescued the RBM5 depletion effects on colony formation and self-renewal gene expression program. Thus, our study shows that RBM5 regulates the AML LSC program through transcriptional regulation and provides a rationale to therapeutically target RBM5 in myeloid leukemia.