Ets1 Phosphorylation At Threonine-38 Is A Marker Of B Cell Receptor Activation, Associating With Cell Of Origin And Outcome In Diffuse Large B Cell Lymphoma

Background. Diffuse large B cell lymphoma (DLBCL) represents the most common lymphoma subtype (30%-40% lymphomas). Gene expression profiling (GEP) identifies two main subtypes of DLBCL defined by their postulated cell of origin (COO). Activated B cell-like DLBCL (ABC DLBCL) is characterized by activation of B-cell receptor signaling and the nuclear factor kB pathway: these patients respond worse to standard R-CHOP but better to novel agents (ibrutinib or lenalidomide) than patients with DLBCL of the germinal-center-type (GCB DLBCL). We have previously reported an upregulation of the transcriptional factor ETS1 in up to 25% of DLBCL (Bonetti, Testoni et al. Blood, 2013). ETS1 is involved in many biologic processes, including B cell differentiation. ETS1 undergoes a series of post-translational modifications, and, in particular, ETS1 phosphorylation at Threonine 38 (p-ETS1) is a marker for ETS1 activation. Here, we present the impact of p-ETS1 in DLBCL cellular models and in a large series of clinical specimens. Patients and Methods. Levels of p-ETS1 (ab59179, Abcam) and, as controls, of ETS1 (C-20, Santa Cruz Biotechnology), ERK (93, Santa Cruz Biotechnology), p-ERK-Tyr204 (p-ERK; 7383, Santa Cruz Biotechnology) and IRF4 (4964, Cell Signaling Technology) were analyzed in cell lines derived from ABC (n.=7), GCB (n.=8) and type 3 (n.=4) DLBCL. p-ETS1 was examined by immunohistochemistry on clinical specimens: cases were defined as positive if u003e 10% of the neoplastic cells nuclei were p-ETS1 positive. Results. p-ETS1 was detected in ABC, not in GCB DLBCL cell lines (100% vs 0%, P Conclusions. Our data identify ETS1 phosphorylation at threonine 38 as i) associated with the ABC DLBCL phenotype; ii) associated with poor PFS in GCB DLBCL; iii) downstream to BCR signaling and amenable to pharmacological interventions with BTK and MEK inhibitors. Disclosures Rossi: Gilead: Honoraria, Research Funding; Abbvie: Honoraria; Janseen: Honoraria.