Targeting RBPMS selectively eliminates leukemia initiating cells via the USP1/m6A/FOXO1 axis

Acute myeloid leukemia (AML) is a malignant tumor with high recurrence rate and poor prognosis. RNA-binding proteins (RBPs) are essential modulators of transcription and translation played critical roles and frequently dysregulated in AML. Here we show that RBPMS (RNA binding protein with multiple splicing) which is highly expressed in AML and associated with poor prognosis of AML, plays critical roles in leukemogenesis. Our study shows that inhibition of RBPMS abrogates self-renewal of leukemia initiating cells (LICs) and AML development but has little effect on normal hematopoiesis. Mechanistically, RBPMS maintains the stability of the m6A reader IGF2BP3 by USP1-mediated deubiquitination, which promotes the translation of the FOXO1 mRNA in an m6A-dependent manner. Moreover, RBPMS contributes to the progression of leukemia by promoting FOXO1/ENO2/ALDOC regulated glycolysis. Overexpression of FOXO1 has been shown to rescue RBPMS inhibition-induced phenotypes in both leukemia cells and mouse models. We have also designed a specific inhibitor of RBPMS that has therapeutic effects in the AML patient derived xenograft model (PDX) model. We, therefore, we highlight RBPMS as a promising drug target for AML therapy. Overall design: Suppression of RBPMS by shRNA in Kasumi-1 cells, as well as the control cells were subjected to RNA-seq.Treatment with RB98# in Kasumi-1 cells, as well as the control cells were subjected to RNA-seq. RIP-seq of HA RBPMS was performed with HA antibody in Kasumi-1 cells , and rabbit IgG as the control. m6A-seq of Kasumi-1 cells was performed with m6A antibody.