SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma.

Mantle cell lymphoma (MCL) is one of the most aggressive lymphoid neoplasms whose pathogenesis is not fully understood. The neural transcription factor SOX11 is overexpressed in most MCL but is not detected in other mature B-cell lymphomas or normal lymphoid cells. The specific expression of SOX11 in MCL suggests that it may be an important element in the development of this tumor, but its potential function is not known. Here, we show that SOX11 promotes tumor growth in a MCL-xenotransplant mouse model. Using chromatin immunoprecipitation microarray analysis combined with gene expression profiling upon SOX11 knockdown, we identify target genes and transcriptional programs regulated by SOX11 including the block of mature B-cell differentiation, modulation of cell cycle, apoptosis, and stem cell development. PAX5 emerges as one of the major SOX11 direct targets. SOX11 silencing downregulates PAX5, induces BLIMP1 expression, and promotes the shift from a mature B cell into the initial plasmacytic differentiation phenotype in both primary tumor cells and an in vitro model. Our results suggest that SOX11 contributes to tumor development by altering the terminal B-cell differentiation program of MCL and provide perspectives that may have clinical implications in the diagnosis and design of new therapeutic strategies.

[1]  E. Giné,et al.  Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features. , 2012, Cancer research.

[2]  B. Sander,et al.  Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma. , 2012, Blood.

[3]  E. Giné,et al.  Non-nodal type of mantle cell lymphoma is a specific biological and clinical subgroup of the disease , 2012, Leukemia.

[4]  R. Sandberg,et al.  Sequentially acting Sox transcription factors in neural lineage development. , 2011, Genes & development.

[5]  K. Tarte,et al.  Characterization of a Transitional Preplasmablast Population in the Process of Human B Cell to Plasma Cell Differentiation , 2011, The Journal of Immunology.

[6]  R. Lai,et al.  Indolent mantle cell leukemia: a clinicopathological variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, kappa light chain restriction, and good prognosis , 2011, Haematologica.

[7]  A. Rosenwald,et al.  Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications , 2011, PloS one.

[8]  Markus Jaritz,et al.  The transcription factor Pax5 regulates its target genes by recruiting chromatin‐modifying proteins in committed B cells , 2011, The EMBO journal.

[9]  S. Nutt,et al.  Germinal center B and follicular helper T cells: siblings, cousins or just good friends? , 2011, Nature Immunology.

[10]  W. Chan,et al.  Molecular Characteristics of Mantle Cell Lymphoma Presenting With Clonal Plasma Cell Component , 2011, The American journal of surgical pathology.

[11]  E. Campo,et al.  The Hsp90 inhibitor IPI-504 overcomes bortezomib resistance in mantle cell lymphoma in vitro and in vivo by down-regulation of the prosurvival ER chaperone BiP/Grp78. , 2011, Blood.

[12]  L. Staudt,et al.  Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation. , 2011, Blood.

[13]  Govind Bhagat,et al.  BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. , 2010, Cancer cell.

[14]  A. Rosenwald,et al.  Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. , 2010, Cancer research.

[15]  Elin Gustavsson,et al.  Strong lymphoid nuclear expression of SOX11 transcription factor defines lymphoblastic neoplasms, mantle cell lymphoma and Burkitt’s lymphoma , 2009, Haematologica.

[16]  L. Staudt,et al.  SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype , 2009, Haematologica.

[17]  M. Covic,et al.  Expression of Sox11 in adult neurogenic niches suggests a stage‐specific role in adult neurogenesis , 2009, The European journal of neuroscience.

[18]  M. D. Den Boer,et al.  Differential expression and prognostic significance of SOX genes in pediatric medulloblastoma and ependymoma identified by microarray analysis. , 2008, Neuro-oncology.

[19]  Véronique Lefebvre,et al.  The three SoxC proteins—Sox4, Sox11 and Sox12—exhibit overlapping expression patterns and molecular properties , 2008, Nucleic acids research.

[20]  Andreas Radbruch,et al.  Plasma cell differentiation and survival. , 2008, Current opinion in immunology.

[21]  Karin Jirström,et al.  From bloodjournal.hematologylibrary.org at PENN STATE UNIVERSITY on February 28, 2013. For personal use only. , 2006 .

[22]  E. Campo,et al.  Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics , 2007, Nature Reviews Cancer.

[23]  M. Busslinger,et al.  Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors , 2007, Nature.

[24]  Jhagvaral Hasbold,et al.  Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1. , 2007, Immunity.

[25]  W. Chan,et al.  Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas. , 2006, Blood.

[26]  L. Staudt,et al.  A library of gene expression signatures to illuminate normal and pathological lymphoid biology , 2006, Immunological reviews.

[27]  J. Buerstedde,et al.  Loss of Pax5 promotes plasma cell differentiation. , 2006, Immunity.

[28]  Stefano Monti,et al.  Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma , 2006, The Journal of experimental medicine.

[29]  E. Campo,et al.  Mantle cell lymphoma: from pathology and molecular pathogenesis to new therapeutic perspectives. , 2006, Haematologica.

[30]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Gabriele Schackert,et al.  Highly specific overexpression of the transcription factor SOX11 in human malignant gliomas. , 2005, Oncology reports.

[32]  Ernst R. Tamm,et al.  Gene Targeting Reveals a Widespread Role for the High-Mobility-Group Transcription Factor Sox11 in Tissue Remodeling , 2004, Molecular and Cellular Biology.

[33]  M. Sigvardsson,et al.  The roles of transcription factors in B lymphocyte commitment, development, and transformation , 2004, Journal of leukocyte biology.

[34]  K. Tarte,et al.  Gene expression profiling of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell differentiation. , 2003, Blood.

[35]  D. Catovsky,et al.  A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease. , 2003, Blood.

[36]  A. Rizzino,et al.  Identification of Novel Domains within Sox-2 and Sox-11 Involved in Autoinhibition of DNA Binding and Partnership Specificity* , 2003, The Journal of Biological Chemistry.

[37]  Liming Yang,et al.  Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. , 2002, Immunity.

[38]  O. Haas,et al.  Deregulated PAX-5 transcription from a translocated IgH promoter in marginal zone lymphoma. , 1998, Blood.

[39]  M. Busslinger,et al.  Deregulation of PAX-5 by translocation of the Emu enhancer of the IgH locus adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[40]  R. Dalla‐Favera,et al.  The t(9;14)(p13;q32) chromosomal translocation associated with lymphoplasmacytoid lymphoma involves the PAX-5 gene. , 1996, Blood.

[41]  H. Clevers,et al.  Sox‐4, an Sry‐like HMG box protein, is a transcriptional activator in lymphocytes. , 1993, The EMBO journal.