Smurf2 mediates ubiquitination and degradation of YY1 to suppress B-cell proliferation and lymphomagenesis (P2181)

Abstract

Abstract Current treatment of diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin’s lymphoma, has improved patient survival significantly. However, 40-50% of DLBCL patients still die from this disease. There is a critical need to better understand the specific molecular pathways that are perturbed in DLBCL for the development of new therapeutic approaches. Using a mouse model deficient in the E3 ubiquitin ligase Smurf2, we show that Smurf2 deficiency increases the susceptibility of these mice to spontaneous B-cell lymphomagenesis. Lymphomas developed in Smurf2-deficient mice resemble human DLBCL with molecular features of germinal center B cells. We discover that Smurf2 mediates ubiquitination and degradation of YY1, a key germinal center transcription factor. Importantly, loss of Smurf2 enhances YY1-mediated transactivation of c-Myc and B-cell proliferation. Furthermore, we find that expression of Smurf2 is significantly decreased in primary human DLBCL samples compared to normal B cells. Importantly, low levels of Smurf2 expression correlate with poor survival prognosis in DLBCL patients. The Smurf2-YY1-c-Myc regulatory axis represents a novel pathway perturbed in DLBCL that suppresses B-cell proliferation and lymphomagenesis, and identifies Smurf2 as a new therapeutic paradigm for DLBCL.