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

Author:

Lin Tasha L.1,Jaiswal Amit K.2,Ritter Alexander J.3ORCID,Reppas Jenna2,Tran Tiffany M.24,Neeb Zachary T.3ORCID,Katzman Sol5,Thaxton Michelle L.2,Cohen Amanda2,Sanford Jeremy R.35ORCID,Rao Dinesh S.267ORCID

Affiliation:

1. 1Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA

2. 2Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA

3. 3Department of Molecular, Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, CA

4. 4Department of Medicine, University of California, Los Angeles, Los Angeles, CA

5. 5Center for Biomolecular Science & Engineering, University of California Santa Cruz, Santa Cruz, CA

6. 6Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA

7. 7Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA

Abstract

Abstract RNA-binding proteins (RBPs) are emerging as a novel class of therapeutic targets in cancer, including in leukemia, given their important role in posttranscriptional gene regulation, and have the unexplored potential to be combined with existing therapies. The RBP insulin-like growth factor 2 messenger RNA–binding protein 3 (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 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 small molecule MI-503 alone and showed enhanced antileukemic effects in combination. Our work shows that IGF2BP3 is an oncogenic amplifier of MLL-AF4–mediated leukemogenesis and a potent therapeutic target, providing a paradigm for targeting leukemia at both the transcriptional and posttranscriptional level.

Publisher

American Society of Hematology

Subject

Hematology

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