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Regulation of SOX11 expression through CCND1 and STAT3 in mantle cell lymphoma

Mohanty, Atish and Sandoval, Natalie and Phan, An and Nguyen, Thang V. and Chen, Robert W. and Budde, Elizabeth and Mei, Matthew and Popplewell, Leslie and Pham, Lan V. and Kwak, Larry W. and Weisenburger, Dennis D. and Rosen, Steven T. and Chan, Wing C. and Müschen, Markus and Ngo, Vu N. (2019) Regulation of SOX11 expression through CCND1 and STAT3 in mantle cell lymphoma. Blood, 133 (4). pp. 306-318. ISSN 0006-4971.

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The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)–induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11^+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL.

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Mei, Matthew0000-0002-1109-6955
Additional Information:© 2018 American Society of Hematology. Submitted 16 May 2018; accepted 30 November 2018. Prepublished online as Blood First Edition paper, 10 December 2018; DOI 10.1182/blood-2018-05-851667. This work was supported in part by National Institutes of Health, National Cancer Institute Cancer Center Support Grant P30CA033572 to the City of Hope, by the American Society of Hematology, by the Gabrielle’s Angel Foundation for Cancer Research, and by Department of Defense Grant CA140945 (V.N.N.). Authorship: Contribution: A.M. and V.N.N. designed the experiments; A.M., N.S., A.P., and V.N.N. performed the experiments; A.M., M. Mei, and V.N.N. analyzed data; T.V.N. provided essential research reagents; R.W.C., E.B., M. Mei, L.P., L.V.P., L.W.K., D.D.W., S.T.R., W.C.C., and M. Müschen provided and reviewed pathological data; D.D.W. edited the manuscript; and V.N.N. directed the research and wrote the manuscript. The authors declare no competing financial interests. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Funding AgencyGrant Number
American Society of HematologyUNSPECIFIED
Gabrielle’s Angel Foundation for Cancer ResearchUNSPECIFIED
Department of DefenseCA140945
Issue or Number:4
Record Number:CaltechAUTHORS:20181221-105357612
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Official Citation:Regulation of SOX11 expression through CCND1 and STAT3 in mantle cell lymphoma. Atish Mohanty, Natalie Sandoval, An Phan, Thang V. Nguyen, Robert W. Chen, Elizabeth Budde, Matthew Mei, Leslie Popplewell, Lan V. Pham, Larry W. Kwak, Dennis D. Weisenburger, Steven T. Rosen, Wing C. Chan, Markus Müschen, Vu N. Ngo. Blood Jan 2019, 133 (4) 306-318; DOI: 10.1182/blood-2018-05-851667
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:91960
Deposited By: George Porter
Deposited On:21 Dec 2018 20:04
Last Modified:03 Oct 2019 20:39

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