title: SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma.
abstract: 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.
authors: Hematopathology Unit, Pathology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
authors: Maria Carmela
authors: MC
authors: Vegliante
authors: Jara
authors: J
authors: Palomero
authors: Patricia
authors: P
authors: Pérez-Galán
authors: Gaël
authors: G
authors: Roué
authors: Giancarlo
authors: G
authors: Castellano
authors: Alba
authors: A
authors: Navarro
authors: Guillem
authors: G
authors: Clot
authors: Alexandra
authors: A
authors: Moros
authors: Helena
authors: H
authors: Suárez-Cisneros
authors: Sílvia
authors: S
authors: Beà
authors: Luis
authors: L
authors: Hernández
authors: Anna
authors: A
authors: Enjuanes
authors: Pedro
authors: P
authors: Jares
authors: Neus
authors: N
authors: Villamor
authors: Dolors
authors: D
authors: Colomer
authors: José Ignacio
authors: JI
authors: Martín-Subero
authors: Elias
authors: E
authors: Campo
authors: Virginia
authors: V
authors: Amador
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D051757:PAX5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C097473:SOX11 protein, human; D055751:SOXC Transcription Factors