FOXP1 and ARID3A Collaborate to Activate Transcription of Core Embryonic Stem Cell Factors in Activated B-Cell Diffuse Large B cell Lymphoma

Embryonic development requires establishment of networks of stem cells via coordination of “Core” transcription factors (OCT4, SOX2, KLF4, NANOG and c-MYC; abbreviated as OSKNM) with a complex array of auxiliary and epigenetic modulators. We showed previously that down regulation of the ARID3A transcription factor is critical for embryonic stem cell (ESC) growth and differentiation to trophectoderm via direct transcriptional repression of OSKNM. FOXP1 and ARID3Aare two differentially expressed genes that define the most aggressive, Activated B Cell subset of Diffuse Large B Cell Lymphoma (ABC-DLBCL). FOXP1, a well-documented “gold standard of the ABC-subtype, more recently was identified as a regulator of pluripotency, whereas ARID3A function in ES biology is well documented. We demonstrate here that ARID3A is a directly activated target ofFOXP1. Reduction of ARID3Aexpression in ABC-DLBCL tumors, but not in the more benign, Germinal Center (GCB-DLBCL) subset, leads to loss of proliferation and down regulation of several OSKNM factors. Our results suggest that modulation of ARID3A levels may provide both prognostic and therapeutic options for a malignancy representing the most prevalent and aggressive non-Hodgkin's lymphoma worldwide.