Rbm5 sustains leukemia stem cells through a Myc-driven transcriptional circuitry.

Abstract

Acute myeloid leukemia (AML) represents a type of malignant hematological disease that is usually caused by the dysregulated developmental program of leukemia stem cells (LSCs). Here, we report that an unappreciated RNA-binding protein, Rbm5, selectively promotes murine leukemogenesis, maintains LSC self-renewal in vivo, and is dispensable for normal hematopoiesis. Rbm5 is highly expressed in LSCs, and its deficiency results in specifically defective LSC function, along with inhibition of self-renewal gene expression and induction of myeloid differentiation. Multi-disciplinary mechanistic investigations further identified Myc as the major and direct transcriptional target of Rbm5 in primary leukemia cells. Moreover, RBM5 not only interacts with MYC but also maintains its protein levels, thereby sustaining the Myc downstream transcriptional network through its proper genome-wide occupancy. Forced expression of Myc sufficiently rescued the Rbm5-depleted LSC defects. Thus, our study demonstrates that Rbm5 regulates the AML LSC program through non-canonical transcriptional mechanisms, providing a strong rationale for targeting Rbm5 therapeutically. In Brief. Zhang et al. illustrate the role of Rbm5 in sustaining the self-renewal program in leukemia stem. cells (LSCs) primarily through the Myc transcriptional network. Specifically, Rbm5 loss results in a significant decrease in Myc protein levels, thereby disrupting. the Myc downstream transcriptional network in LSCs. Notably, this effect is specific to LSCs, as. normal hematopoietic stem cells (HSCs) do not exhibit such changes upon Rbm5 loss.