Yadira M Soto-Feliciano, Francisco J Sánchez-Rivera, Florian Perner, Douglas W Barrows, Edward R Kastenhuber, Yu-Jui Ho, Thomas Carroll, Yijun Xiong, Disha Anand, Alexey A Soshnev, Leah Gates, Mary Clare Beytagh, David Cheon, Shengqing Gu, X Shirley Liu, Andrei V Krivtsov, Maximiliano Meneses, Elisa de Stanchina, Richard M Stone, Scott A Armstrong, Scott W Lowe, C David Allis
UNLABELLED: Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin-modifying complexes that dictates response to Menin-MLL inhibitors. MLL1-Menin safeguards leukemia survival by impeding the binding of the MLL3/4-UTX complex at a subset of target gene promoters...
January 9, 2023: Cancer Discovery