Targeting IGF2BP3 enhances antileukemic effects of menin-MLL inhibition in MLL-AF4 leukemia.

RNA binding proteins (RBPs) 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 RBP IGF2BP3 has been found to be a critical regulator of MLL-AF4 leukemogenesis and represents a promising therapeutic target. Here, we study the combined effects of targeting IGF2BP3 and the menin-MLL interaction in MLL-AF4 driven leukemia in vitro and in vivo, using genetic inhibition with CRISPR-Cas9 mediated deletion of Igf2bp3 and pharmacologic inhibition of the menin-MLL interaction with multiple commercially available inhibitors. Depletion of Igf2bp3 sensitized MLL-AF4 leukemia to the effects of menin-MLL inhibition on cell growth and leukemic initiating cells in vitro. Mechanistically, we found that both Igf2bp3 depletion and menin-MLL inhibition led to increased differentiation in vitro and in vivo, seen in functional readouts and by gene expression analyses. IGF2BP3 knockdown had a greater effect on increasing survival and attenuating disease than pharmacologic menin-MLL inhibition with MI-503 alone and showed enhanced anti-leukemic effects in combination. Our work shows that IGF2BP3 is an oncogenic amplifier of MLL-AF4 mediated leukemogenesis and is a potent therapeutic target and provides a paradigm for targeting leukemia at both the transcriptional and post-transcriptional level.

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