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

Samantha M Bevill; Salvador Casaní-Galdón; Chadi A El Farran; Eli G Cytrynbaum; Kevin A Macias; Sylvie E Oldeman; Kayla J Oliveira; Molly M Moore; Esmat Hegazi; Carmen Adriaens; Fadi J Najm; George D Demetri; Sonia Cohen; John T Mullen; Nicolò Riggi; Sarah E Johnstone; Bradley E Bernstein

doi:10.1016/j.xgen.2023.100321

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

Cell Genom. 2023 May 11;3(7):100321. doi: 10.1016/j.xgen.2023.100321. eCollection 2023 Jul 12.

Authors

Samantha M Bevill^{1

2

3}, Salvador Casaní-Galdón^{1

2

3}, Chadi A El Farran^{1

2

3}, Eli G Cytrynbaum^{2

3

4}, Kevin A Macias^{1

2

3}, Sylvie E Oldeman^{1

3}, Kayla J Oliveira^{2

5}, Molly M Moore², Esmat Hegazi^{2

3

4}, Carmen Adriaens^{1

2

3}, Fadi J Najm², George D Demetri^{6

7}, Sonia Cohen^{1

2

3

8}, John T Mullen⁸, Nicolò Riggi⁹, Sarah E Johnstone^{2

5}, Bradley E Bernstein^{1

2

3

7}

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁵ Department of Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
⁷ Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
⁸ Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Department of Cell and Tissue Genomics (CTG), Genentech Inc, South San Francisco, CA 94080, USA.

Abstract

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.

Keywords: MDM2; P53 independent; epigenetics; genome topology; liposarcoma; sarcoma; therapeutic resistance.

Abstract

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