Combined inhibition of transcriptional and IGF2BP3-driven post-transcriptional gene regulation in MLL-AF4 leukemogenesis

RNA binding proteins are emerging as a novel class of therapeutic targets in cancer, including in leukemia, given their important role in post-transcriptional gene regulation, and have the unexplored potential to be combined with existing therapies. The RNA binding protein IGF2BP3 has been found to be a critical regulator of MLL-AF4 leukemogenesis and represents a promising therapeutic target. In our present study, we look at the combined effects of targeting IGF2BP3 and the menin-MLL interaction in MLL-AF4 driven leukemia, using genetic inhibition with CRISPR-Cas9 mediated deletion of Igf2bp3 and pharmacologic inhibition of the menin-MLL interaction with the commercially available inhibitor, MI-503. RNA-seq analysis was performed in MLL-Af4 transformed hematopoietic stem and progenitor cells (HSPCs and referred to as MLL-Af4 Lin- cells) depleted for IGF2BP3 and treated with menin-MLL inhibitor MI-503, to evaluate how combined menin-MLL inhibition and IGF2BP3 knockdown interact and affect gene expression. Analysis of changes in gene expression provide potential mechanistic insights on how combined inhibition of IGF2BP3 and menin-MLL lead to enhanced anti-leukemic effects and form the basis for a novel combinatorial therapeutic strategy of co-inhibition at the transcriptional and post-transcriptional gene level.