High-resolution chromatin immunoprecipitation (ChIP) sequencing reveals novel binding targets and prognostic role for SOX11 in mantle cell lymphoma

Abstract

SOX11 (Sex determining region Y-box 11) expression is specific for MCL as compared to other Non-Hodgkin's lymphomas. However, the function and direct binding targets of SOX11 in MCL are largely unknown. We used high-resolution ChIP-Seq to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11 target genes. qCHIP and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency (BCCA). Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11 target genes may help explain the impact of SOX11 expression on patient outcomes.

Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma

“…The conclusion that BCR signaling plays a pathogenic role in MCL is consistent with emerging data on the role of SOX11 in this lymphoma. [35][36][37] The transcription factor SOX11 enforces expression of the lineage master regulator PAX5. 1,37 PAX5 maintains the B-cell program and prevents terminal plasma-cell differentiation, thereby preserving the cellular responsiveness to antigen induced activation and proliferation.…”

Impact of Sox11 over-expression in Ba/F3 cells

“…9 However, other studies report reduced cell proliferation upon SOX11 expression in MCL cells. 10,11 The non-malignant, IL-3 dependent pro-B cell line Ba/F3, which does not express immunoglobulins, 12 has previously been used for evaluating the transformation capability of potential oncogenes. 13 Here we used the Ba/F3 cell line to investigate the functional and transcriptional changes resulting from induced Sox11 expression.…”

Emerging role of SOX11 in mantle cell lymphoma

“…73 Further studies using ChIP-seq has pin-pointed WNT signaling as a potential important pathway down-stream of SOX11. 49 In a separate study by Vegliante et al, they suggest that SOX11 blocks terminal B-cell differentiation in aggressive MCL through direct positive regulation of PAX5. 74 It is known that SOX genes are promiscuous in their DNA binding capacity and thus, it is not surprising that several pathways may be affected -but it remains to be determined which ones are of most biological value for MCL pathogenesis (see schematic illustration in Figure 1C).…”

“…46,47 This is in contrary to studies presented by Nygren et al and Kuo et al, which concluded that most of their indolent MCL patients were SOX11 positive. 49,57 Recently, two independent studies associated increased SOX11 expression with improved overall survival in patients treated with either the Nordic protocol 22 ( Figure 1A) or with R-Hyper-CVAD 49 pin-pointing a role of SOX11 as a predictive biomarker for these treatments.…”

“…Subsequently, novel methods and improved tools have been developed to be able to clinically use this biomarker for diagnostic and prognostic purposes. Among others, qPCR-based detection of SOX11 48 and methods to analyze fine needle aspirates 49 have been developed. It has further been suggested that SOX11 may be used as a marker for minimal residual disease.…”