Ernst Laboratory - Distinct Pathways Affected by Menin versus

Journal article

Yufei Chen, Kenneth L. Jones, K. Anastassiadis, A. Kranz, A. Stewart, J. Grembecka, M. Meyerson, P. Ernst
Experimental Hematology, 2018

Semantic Scholar DOI PubMedCentral PubMed

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APA Click to copy
Chen, Y., Jones, K. L., Anastassiadis, K., Kranz, A., Stewart, A., Grembecka, J., … Ernst, P. (2018). Distinct Pathways Affected by Menin versus MLL1/MLL2 in MLL-rearranged Acute Myeloid Leukemia. Experimental Hematology.

Chicago/Turabian Click to copy
Chen, Yufei, Kenneth L. Jones, K. Anastassiadis, A. Kranz, A. Stewart, J. Grembecka, M. Meyerson, and P. Ernst. “Distinct Pathways Affected by Menin versus MLL1/MLL2 in MLL-Rearranged Acute Myeloid Leukemia.” Experimental Hematology (2018).

MLA Click to copy
Chen, Yufei, et al. “Distinct Pathways Affected by Menin versus MLL1/MLL2 in MLL-Rearranged Acute Myeloid Leukemia.” Experimental Hematology, 2018.

BibTeX Click to copy

@article{yufei2018a,
  title = {Distinct Pathways Affected by Menin versus MLL1/MLL2 in MLL-rearranged Acute Myeloid Leukemia},
  year = {2018},
  journal = {Experimental Hematology},
  author = {Chen, Yufei and Jones, Kenneth L. and Anastassiadis, K. and Kranz, A. and Stewart, A. and Grembecka, J. and Meyerson, M. and Ernst, P.}
}

Abstract

Disrupting 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 MLL fusion proteins (FPs) have shown significant promise in pre-clinical models of leukemia and show a high degree of selectivity for leukemia versus normal hematopoietic cells. Biochemical and structural studies demonstrate that, in addition to disrupting 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 anti-leukemia effect of Menin inhibition. We show that Men1 deletion in MLL-AF9-transformed leukemia cells produces distinct cellular and molecular consequences as compared to 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 consistent with each regulating complementary genetic pathways. These data illustrate the heightened dependency of MLL-FPs on Menin, as compared to 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.