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.

Plasma cell and terminal B-cell differentiation in mantle cell lymphoma mainly occur in the SOX11-negative subtype

“…[14][15][16] SOX11 knockdown in mantle cell lymphoma cell lines resulted in PAX5 downregulation, increased expression of BLIMP1 and XBP1 and a switch in the gene expression signatures from a mature B-cell to an early plasmacytic differentiation profiling. 13 These findings suggested that SOX11 could contribute to mantle cell lymphoma lymphomagenesis by blocking the terminal B-cell differentiation program of the cells as a similar mechanism observed in the inactivating mutations of PRDM1/BLIMP1 in diffuse large B-cell lymphoma or the forced expression of PAX5 by the t (9;14)(p13;q32) in some B-cell lymphomas. [17][18][19] However, whether primary mantle cell lymphoma may modulate terminal B-cell differentiation features in relation to SOX11 expression is not well known.…”

“…10,11 The oncogenic potential of SOX11 has been confirmed experimentally by SOX11-knockdown studies that have shown a significant reduction of tumor growth in vivo of xenografted SOX11-negative mantle cell lymphoma cell lines. 12,13 The oncogenic mechanisms of SOX11 in mantle cell lymphoma pathogenesis are not well understood. We have recently shown that PAX5 is one of the genes directly regulated by SOX11 in these tumor cells.…”

“…We have recently shown that PAX5 is one of the genes directly regulated by SOX11 in these tumor cells. 13 PAX5 is a critical transcription factor that determines and maintains the B-cell identity by activating B-cellspecific genes and simultaneously repressing genes that promote plasma cell differentiation. [14][15][16] SOX11 knockdown in mantle cell lymphoma cell lines resulted in PAX5 downregulation, increased expression of BLIMP1 and XBP1 and a switch in the gene expression signatures from a mature B-cell to an early plasmacytic differentiation profiling.…”

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

“…Paradoxically, a subset of patients follows an indolent clinical evolution with stable disease even in the absence of chemotherapy (6,7). This favorable behavior has been associated with IGHV-mutated (8,9) and lack of expression of SOX11 (10, 11), a transcription factor highly specific of MCL that contributes to the aggressive behavior of this tumor (12). However, the molecular mechanisms responsible for this clinical heterogeneity are not well understood.…”

Primary mantle cell lymphoma of tonsil: Case report

“…Неки тумори имају додатне алтерације у генима попут ТП53, што води агресивнијој прогресији болести 12,14,15 . Одсуство SOX11 или низак Ki-67 су у узајамном односу са неагресивном формом MCL; SOX11 производи туморски раст MCL ћелија и регулише транскрипцију 17 . Једна од најснажнијих директних мета SOH11 je PAX5, главни регулатор диференцијације B-ћелија.…”