Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation

Abstract MYC upregulation is associated with multidrug refractory disease in patients with multiple myeloma (MM). We, isolated patient-derived MM cells with high MYC expression and discovered that NCOR2 was down-regulated in these cells. NCOR2 is a transcriptional coregulatory protein and its role i...

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Autores principales:	Tomoaki Mori, Rakesh Verma, Rie Nakamoto-Matsubara, Ka Tat Siu, Cristina Panaroni, Keertik S. Fulzele, Kenta Mukaihara, Chukwuamaka Onyewadume, Allison Maebius, Hiroki Kato, Lai Ping Wong, Ruslan I. Sadreyev, David T. Scadden, Noopur S. Raje
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/b338d530f2da4568b81bbdf194813434
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spelling	oai:doaj.org-article:b338d530f2da4568b81bbdf1948134342021-12-05T12:25:50ZLow NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation10.1038/s41408-021-00589-y2044-5385https://doaj.org/article/b338d530f2da4568b81bbdf1948134342021-12-01T00:00:00Zhttps://doi.org/10.1038/s41408-021-00589-yhttps://doaj.org/toc/2044-5385Abstract MYC upregulation is associated with multidrug refractory disease in patients with multiple myeloma (MM). We, isolated patient-derived MM cells with high MYC expression and discovered that NCOR2 was down-regulated in these cells. NCOR2 is a transcriptional coregulatory protein and its role in MM remains unknown. To define the role of NCOR2 in MM, we created NCOR2 knockout human myeloma cell lines and demonstrated that NCOR2 knockout led to high MYC expression. Furthermore, NCOR2 knockout conferred resistance to pomalidomide, BET and HDAC inhibitors, independent of Cereblon (CRBN), indicating high MYC expression as a cause of multidrug resistance. Moreover, NCOR2 interacted with the nucleosome remodeling and deacetylase (NuRD) complex and repressed the expression of CD180 by directly binding to its promoter and inducing MYC expression. Next, we generated lenalidomide-resistant and pomalidomide-resistant human myeloma cell lines. Whole-exome sequencing revealed that these cell lines acquired the same exonic mutations of NCOR2. These cell lines showed NCOR2 downregulation and MYC upregulation independent of CRBN and demonstrated resistance to BET and HDAC inhibitors. Our findings reveal a novel CRBN independent molecular mechanism associated with drug resistance. Low NCOR2 expression can serve as a potential biomarker for drug resistance and needs further validation in larger prospective studies.Tomoaki MoriRakesh VermaRie Nakamoto-MatsubaraKa Tat SiuCristina PanaroniKeertik S. FulzeleKenta MukaiharaChukwuamaka OnyewadumeAllison MaebiusHiroki KatoLai Ping WongRuslan I. SadreyevDavid T. ScaddenNoopur S. RajeNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBlood Cancer Journal, Vol 11, Iss 12, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Tomoaki Mori Rakesh Verma Rie Nakamoto-Matsubara Ka Tat Siu Cristina Panaroni Keertik S. Fulzele Kenta Mukaihara Chukwuamaka Onyewadume Allison Maebius Hiroki Kato Lai Ping Wong Ruslan I. Sadreyev David T. Scadden Noopur S. Raje Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation
description	Abstract MYC upregulation is associated with multidrug refractory disease in patients with multiple myeloma (MM). We, isolated patient-derived MM cells with high MYC expression and discovered that NCOR2 was down-regulated in these cells. NCOR2 is a transcriptional coregulatory protein and its role in MM remains unknown. To define the role of NCOR2 in MM, we created NCOR2 knockout human myeloma cell lines and demonstrated that NCOR2 knockout led to high MYC expression. Furthermore, NCOR2 knockout conferred resistance to pomalidomide, BET and HDAC inhibitors, independent of Cereblon (CRBN), indicating high MYC expression as a cause of multidrug resistance. Moreover, NCOR2 interacted with the nucleosome remodeling and deacetylase (NuRD) complex and repressed the expression of CD180 by directly binding to its promoter and inducing MYC expression. Next, we generated lenalidomide-resistant and pomalidomide-resistant human myeloma cell lines. Whole-exome sequencing revealed that these cell lines acquired the same exonic mutations of NCOR2. These cell lines showed NCOR2 downregulation and MYC upregulation independent of CRBN and demonstrated resistance to BET and HDAC inhibitors. Our findings reveal a novel CRBN independent molecular mechanism associated with drug resistance. Low NCOR2 expression can serve as a potential biomarker for drug resistance and needs further validation in larger prospective studies.
format	article
author	Tomoaki Mori Rakesh Verma Rie Nakamoto-Matsubara Ka Tat Siu Cristina Panaroni Keertik S. Fulzele Kenta Mukaihara Chukwuamaka Onyewadume Allison Maebius Hiroki Kato Lai Ping Wong Ruslan I. Sadreyev David T. Scadden Noopur S. Raje
author_facet	Tomoaki Mori Rakesh Verma Rie Nakamoto-Matsubara Ka Tat Siu Cristina Panaroni Keertik S. Fulzele Kenta Mukaihara Chukwuamaka Onyewadume Allison Maebius Hiroki Kato Lai Ping Wong Ruslan I. Sadreyev David T. Scadden Noopur S. Raje
author_sort	Tomoaki Mori
title	Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation
title_short	Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation
title_full	Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation
title_fullStr	Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation
title_full_unstemmed	Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation
title_sort	low ncor2 levels in multiple myeloma patients drive multidrug resistance via myc upregulation
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/b338d530f2da4568b81bbdf194813434
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Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation

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