A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin-MLL Inhibition.

Autor:	Soto-Feliciano YM; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York., Sánchez-Rivera FJ; Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Perner F; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.; Internal Medicine C, Greifswald University Medical Center, Greifswald, Germany., Barrows DW; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York.; Bioinformatics Resource Center, The Rockefeller University, New York, New York., Kastenhuber ER; Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Ho YJ; Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Carroll T; Bioinformatics Resource Center, The Rockefeller University, New York, New York., Xiong Y; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts., Anand D; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Internal Medicine C, Greifswald University Medical Center, Greifswald, Germany., Soshnev AA; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York., Gates L; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York., Beytagh MC; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York., Cheon D; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York., Gu S; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts.; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Liu XS; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts.; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Krivtsov AV; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts., Meneses M; Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York., de Stanchina E; Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York., Stone RM; Leukemia Division, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Armstrong SA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts., Lowe SW; Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Allis CD; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2023 Jan 09; Vol. 13 (1), pp. 146-169.
DOI:	10.1158/2159-8290.CD-22-0416
Abstrakt:	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. Disrupting the Menin-MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are insensitive to Menin inhibitors. These findings shed light on novel functions of evolutionarily conserved epigenetic mediators like MLL1-Menin and MLL3/4-UTX and are relevant to understand and target molecular pathways determining therapeutic responses in ongoing clinical trials. Significance: Menin-MLL inhibitors silence a canonical HOX- and MEIS1-dependent oncogenic gene expression program in leukemia. We discovered a parallel, noncanonical transcriptional program involving tumor suppressor genes that are repressed in Menin-MLL inhibitor-resistant leukemia cells but that can be reactivated upon combinatorial treatment with CDK4/6 inhibitors to augment therapy responses. This article is highlighted in the In This Issue feature, p. 1. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu