The genomic landscape of canine diffuse large B-cell lymphoma identifies distinct subtypes with clinical and therapeutic implications

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid neoplasm in dogs, being characterized by a remarkable degree of clinical heterogeneity not completely explained by molecular data. This poses a major barrier to understanding the disease and response to therapy or when using dogs with DLBCL in clinical trials. We performed an integrated analysis of genome, exome and RNA sequencing in a cohort of 77 canine DLBCL to define the genetic landscape of this tumor. A wide range of signaling pathways and cellular processes were found in common with human DLBCL, but the frequencies of the most recurrently mutated genes were different overall. We developed a prognostic model integrating clinical, exonic variants and transcriptomic features to predict outcome in dogs with DLBCL. These results comprehensively define the genetic drivers of canine DLBCL and can be prospectively utilized to identify new therapeutic opportunities.

TRAF3: A novel regulator of mitochondrial physiology and metabolic pathways in B lymphocytes

“…Subsequent studies revealed that deletions and inactivating mutations of TRAF3 are frequently detected in many other types of mature B cell malignancies, including diffuse large B-cell lymphoma (DLBCL), splenic marginal zone lymphoma (MZL), B-cell chronic lymphocytic leukemia (B-CLL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia, and Hodgkin lymphoma (HL) (1,3,(9)(10)(11)30). This is corroborated by frequent TRAF3 mutations detected in canine non-Hodgkin lymphomas (NHL) (31)(32)(33)(34). Similar to Traf3 -/mouse B cells, human B cells with germline TRAF3 mutations that reduce TRAF3 expression also exhibit constitutive NF-kB2 activation and enhanced responses to BCR, BAFF, TLR9, and IL-6 signaling, including increased proliferation and plasma cell formation associated with elevated activation of NF-kB1, ERK, AKT, and STAT3 (14).…”