Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma.

Autor:	Bevill SM; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02115, USA., Casaní-Galdón S; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02115, USA., El Farran CA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02115, USA., Cytrynbaum EG; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02115, USA.; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA., Macias KA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02115, USA., Oldeman SE; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02115, USA., Oliveira KJ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Department of Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Moore MM; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Hegazi E; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02115, USA.; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA., Adriaens C; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02115, USA., Najm FJ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Demetri GD; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA., Cohen S; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02115, USA.; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA., Mullen JT; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA., Riggi N; Department of Cell and Tissue Genomics (CTG), Genentech Inc, South San Francisco, CA 94080, USA., Johnstone SE; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Department of Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Bernstein BE; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02115, USA.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
Jazyk:	angličtina
Zdroj:	Cell genomics [Cell Genom] 2023 May 11; Vol. 3 (7), pp. 100321. Date of Electronic Publication: 2023 May 11 (Print Publication: 2023).
DOI:	10.1016/j.xgen.2023.100321
Abstrakt:	Amplification of MDM2 on supernumerary chromosomes is a common mechanism of P53 inactivation across tumors. Here, we investigated the impact of MDM2 overexpression on chromatin, gene expression, and cellular phenotypes in liposarcoma. Three independent regulatory circuits predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind mesenchymal gene enhancers. P53 and MDM2 co-occupy enhancers and promoters associated with P53 signaling. When highly expressed, MDM2 also binds thousands of P53-independent growth and stress response genes, whose promoters engage in multi-way topological interactions. Overexpressed MDM2 concentrates within nuclear foci that co-localize with PML and YY1 and could also contribute to P53-independent phenotypes associated with supraphysiologic MDM2. Importantly, we observe striking cell-to-cell variability in MDM2 copy number and expression in tumors and models. Whereas liposarcoma cells are generally sensitive to MDM2 inhibitors and their combination with pro-apoptotic drugs, MDM2-high cells tolerate them and may underlie the poor clinical efficacy of these agents. Competing Interests: B.E.B. declares outside interests in Fulcrum Therapeutics, Arsenal Biosciences, HiFiBio, Cell Signaling Technologies, Design Pharmaceuticals, and Chroma Medicine. G.D.D. reports leadership as co-founder of IDRX; stocks/options/shares in IDRX, Blueprint Medicines, G1 Therapeutics, Caris Life Sciences, Erasca Pharmaceuticals, RELAY Therapeutics, Bessor Pharmaceuticals, CellCarta, IKENA Oncology, and Kojin Therapeutics; paid consulting fees from Bayer, Pfizer, Novartis, Roche/Genentech, GSK, PharmaMar, Daiichi Sankyo, EMD-Serono/Merck KGaA, Mirati, WCG/Arsenal Capital, G1 Therapeutics, Caris Life Sciences, RELAY Therapeutics, CellCarta, IKENA Oncology, Kojin Therapeutics, RAIN Therapeutics, Jazz Pharmaceuticals, Aadi Biosciences, and IDRX; royalties, patents, or licenses from Novartis to Dana-Farber Cancer Institute for “use patent” of imatinib in GIST; and non-financial interests in AACR Science Policy and Government Affairs Committee and Alexandria Real Estate Equities summit conference series. (© 2023 The Author(s).)
Databáze:	MEDLINE
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