High ETV6 Levels Support Aggressive B Lymphoma Cell Survival and Predict Poor Outcome in Diffuse Large B-Cell Lymphoma Patients

SIMPLE SUMMARY: B-cell lymphomas are tumors that arise from the proliferation of altered B-cells in lymphoid organs. Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma and is very heterogeneous from a molecular, genetic and clinical point of view. To identify novel therapeutic targets, we compared protein expression levels of selected molecules from biopsies of DLBCL patients with different clinical outcomes. We found that two proteins were particularly important for predicting patient survival. The evaluation of these two proteins improves the capacity to discriminate which patients show prolonged survival or succumb of disease. Furthermore, expression levels of one of these proteins predicts sensitivity to a specific death-inducing drug, suggesting the possibility of personalized treatment. ABSTRACT: The identification of prognostic factors for aggressive B-cell lymphomas still represents an unmet clinical need. We used forward phase protein arrays (FFPA) to identify proteins associated with overall survival (OS) from diagnostic formalin-fixed paraffin-embedded material of diffuse large B-cell lymphoma (DLBCL) patients (n = 47). Univariate Cox regression analysis identified numerous proteins, including immune check-point molecules (PDCD1, PDCD2 and PD1L2) and BCL2 to be significantly associated with OS. However, only ETV6 and PIM2 proteins persisted following multivariate Cox analysis. Independent validation studies by immunohistochemistry and analysis of public gene expression profiles of DLBCL confirmed a prognostic role for high ETV6 and ETV6/PIM2 ratios in DLBCL. ETV6 is a recurrently mutated/deleted gene in DLBCL for which its function in this disease entity is currently unknown. We find that ETV6 is upregulated during oncogenic transformation of germinal center B-cells and that it regulates DLBCL survival, as its acute loss results in marked apoptosis. Fluctuations in survivin (BIRC5) expression levels were associated with this phenomenon. Furthermore, an inverse correlation between ETV6 and BIRC5 expression levels was found and correlated with a response to the BIRC5 inhibitor, YM155. In conclusion, we present evidence for an oncogenic function of ETV6 in DLBCL.