The E3 ubiquitin ligase Smurf2 suppresses c-myc expression and B cell lymphoma in mice (74.4)

Abstract

Abstract The NCI estimates in 2012 there will be 70,130 new cases and 18,940 deaths from non-Hodgkin’s lymphoma (NHL) in the US. Diffuse large B-cell lymphoma (DLBCL) is the most common NHL. This aggressive B-cell lymphoma is heterogeneous, with significant variation in response to treatment. Gene expression profiling identifies biologically distinct subtypes of DLBCL, which correlate with both response to treatment and survival. This suggests the critical importance of sub-type-specific targets in the diagnosis and treatment of DLBCL. The E3 ubiquitin ligase Smurf2 induces senescence in human cells, suggesting it is a tumor suppressor. We discovered that ~30% of mice deficient in Smurf2 develop NHLs with a post-germinal center phenotype resembling human DLBCL. B cells from healthy Smurf2-deficient mice exhibit enhanced proliferation and elevated expression of the oncogene c-myc. We find that Smurf2 mediates ubiquitination of a key transcription factor, which, when stabilized in Smurf2-deficient cells increases c-myc expression. This Smurf2-c-Myc axis represents a novel mechanism by which Smurf2 suppresses cell proliferation and lymphomagenesis. Analysis of gene expression databases reveals a significant decrease in Smurf2 expression in human DLBCL compared to normal B cells. Importantly, low level Smurf2 expression correlates with inferior overall survival in DLBCL patients. These data suggest that Smurf2 is a novel target in the diagnosis and potential treatment of human DLBCL.