NUP98 fusion proteins and KMT2A-MENIN antagonize PRC1.1 to drive gene expression in AML.

Autor:	Heikamp EB; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA., Martucci C; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA., Henrich JA; Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA., Neel DS; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA., Mahendra-Rajah S; Vanderbilt University, College of Arts and Sciences, Nashville, TN 37235, USA., Rice H; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA., Wenge DV; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA., Perner F; Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), 30625 Hannover, Germany., Wen Y; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA., Hatton C; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA., Armstrong SA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA. Electronic address: scott_armstrong@dfci.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Nov 26; Vol. 43 (11), pp. 114901. Date of Electronic Publication: 2024 Oct 30.
DOI:	10.1016/j.celrep.2024.114901
Abstrakt:	Control of stem cell-associated genes by Trithorax group (TrxG) and Polycomb group (PcG) proteins is frequently misregulated in cancer. In leukemia, oncogenic fusion proteins hijack the TrxG homolog KMT2A and disrupt PcG activity to maintain pro-leukemogenic gene expression, though the mechanisms by which oncofusion proteins antagonize PcG proteins remain unclear. Here, we define the relationship between NUP98 oncofusion proteins and the non-canonical polycomb repressive complex 1.1 (PRC1.1) in leukemia using Menin-KMT2A inhibitors and targeted degradation of NUP98 fusion proteins. Eviction of the NUP98 fusion-Menin-KMT2A complex from chromatin is not sufficient to silence pro-leukemogenic genes. In the absence of PRC1.1, key oncogenes remain transcriptionally active. Transition to a repressed chromatin state requires the accumulation of PRC1.1 and repressive histone modifications. We show that PRC1.1 loss leads to resistance to small-molecule Menin-KMT2A inhibitors in vivo. Therefore, a critical function of oncofusion proteins that hijack Menin-KMT2A activity is antagonizing repressive chromatin complexes. Competing Interests: Declaration of interests S.A.A. has been a consultant and/or shareholder for Neomorph, Imago Biosciences, Hyku Therapeutics, C4 Therapeutics, Accent Therapeutics, and Nimbus Therapeutics. S.A.A. has received research support from Janssen and Syndax. S.A.A. is an inventor on a patent related to MENIN inhibition WO/2017/132398A1. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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