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

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Public Summary:
In this article, we examined the question of whether disrupting different, abnormal processes in a blood cancer cell could be combined to provide a stronger effect against the cancer. More specifically, we wanted to know if we could combine effects on different parts of gene expression, which is a collective term for the processes in the cell that result in making all the proteins that define a cell's identity. The first step in gene expression is making messenger RNA from DNA (called transcription), and the second step is making protein from mRNA (translation). Recent advances in the field have led to development of chemical compounds that cause a decrease in transcription in blood cancer cells, some of which are now being used to treat patients. We had previously found that the protein IGF2BP3 impacts mRNA, and may effect translation. By doing so, it seems to help the blood cancer cells grow and divide, and helps blood cancer stem cells survive. Here, we wanted to combine the existing chemical compounds could be combined with IGF2BP3. We found that this was indeed the case, and that the effect of the two together was stronger than either one alone. We found that there were similar changes to gene expression by both, and that there was an effect on blood cancer stem cells. Our results suggest that we can, in theory, combine disrupting these two aspects of gene expression can result in a strong anti-cancer effect. In the future, with the chemical compounds we are developing from the CIRM grant, we should be able to combine them with other existing compounds, with the goal of achieving stronger and more durable anti-cancer effects.
Scientific 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.