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Distinct pathways affected by menin versus MLL1/MLL2 in MLL-rearranged acute myeloid leukemia

•Loss of Men1 has a greater impact on cell cycle progression than Mixed Lineage Leukemia 1; Mixed Lineage Leukemia 2 (Mll1;Mll2) loss.•Loss of Men1 in acute myeloid leukemia (AML) predominantly affects the MLL-AF9-driven leukemogenic program.•Mll1;Mll2 deletion increases AML sensitivity to menin inh...

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Published in:Experimental hematology 2019-01, Vol.69, p.37-42
Main Authors: Chen, Yufei, Jones, Kenneth L., Anastassiadis, Konstantinos, Kranz, Andrea, Stewart, A. Francis, Grembecka, Jolanta, Meyerson, Matthew, Ernst, Patricia
Format: Article
Language:English
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Summary:•Loss of Men1 has a greater impact on cell cycle progression than Mixed Lineage Leukemia 1; Mixed Lineage Leukemia 2 (Mll1;Mll2) loss.•Loss of Men1 in acute myeloid leukemia (AML) predominantly affects the MLL-AF9-driven leukemogenic program.•Mll1;Mll2 deletion increases AML sensitivity to menin inhibitors. Disrupting the protein–protein interaction for molecularly targeted cancer therapeutics can be a challenging but promising strategy. Compounds that disrupt the interaction between menin, a chromatin-binding protein, and oncogenic mixed lineage leukemia fusion proteins (MLL-FPs) have shown significant promise in preclinical models of leukemia and have a high degree of selectivity for leukemia versus normal hematopoietic cells. Biochemical and structural studies demonstrate that, in addition to disrupting the menin–MLL-FP interaction, such compounds also inhibit menin–MLL1, menin–MLL2, and other menin-interacting proteins. Here, we address the degree to which disruption of menin–MLL-FP interactions or menin–MLL1/MLL2 interactions contribute to the antileukemia effect of menin inhibition. We show that Men1 deletion in MLL-AF9-transformed leukemia cells produces distinct cellular and molecular consequences compared with Mll1;Mll2 co-deletion and that compounds disrupting menin–MLL N-terminal interactions largely phenocopy menin loss. Moreover, we show that Mll1;Mll2-deficient leukemia cells exhibit enhanced sensitivity to menin interaction inhibitors, which is consistent with each regulating complementary genetic pathways. These data illustrate the heightened dependency of MLL-FPs on menin compared with wild-type MLL1/MLL2 for regulation of downstream target genes and argue that the predominant action of menin inhibitory compounds is through direct inhibition of MLL-FPs without significant contribution from MLL1/MLL2 inhibition.
ISSN:0301-472X
1873-2399
DOI:10.1016/j.exphem.2018.10.001