Abstract IA31: Modeling and targeting double-hit lymphoma

Abstract

Abstract High-grade B-cell lymphoma with concurrent activation of MYC and BCL2, also known as double-hit lymphoma (DHL), shows dismal prognosis with current front-line therapies (e.g., R-CHOP), calling for the development of new therapeutic regimens. The synergy between MYC and BCL2 in lymphomagenesis is explained by the ability of BCL2 to block the proapoptotic activity of MYC, while leaving intact its proliferative potential; on this basis, we reasoned that compounds that exacerbate MYC-induced apoptosis might cooperate with BCL2 inhibitors in killing DHL cells. We previously observed that genes encoding components of the mitochondrial ribosome were coordinately activated in MYC-driven lymphoma (1) and were critical for tumor maintenance in transgenic mice (2). In line with the genetic data, inhibition of mitochondrial translation with the antibiotic tigecycline was synthetic-lethal with MYC activation and extended lifespan in lymphoma-bearing mice (2). Combining tigecycline with the BCL2 inhibitor venetoclax revealed synergy in the induction of apoptosis in human DHL cell lines, as well as marked antitumoral activity in xenografted mice (3). These preclinical data warrant the repurposing of venetoclax and tigecycline for the treatment of refractory and/or relapsed DHL. By blocking the synthesis of mitochondrially encoded proteins, tigecycline impairs the assembly of the electron-transport chain (ETC) complexes and oxidative phosphorylation. We thus hypothesized that direct ETC inhibitors might also preferentially kill MYC-overexpressing cells and synergize with venetoclax against DHL. We will present data that verify these predictions for IACS-010759, a small-molecule inhibitor of mitochondrial complex I. A current limitation for further preclinical development and mechanistic analysis lies in the lack of a bona fide mouse model of DHL. While the cooperation between MYC and BCL2 in lymphomagenesis was amply documented over almost three decades, the models described so far led to tumor onset at early stages of B-cell ontogeny; as a consequence, no model is available that reliably reproduces the development of DHL from germinal center (GC) B-cells, as observed in the clinic. In order to overcome this limitation, we combined CRE-activated alleles of MYC and BCL2 with Cgamma1-CRE, a CRE-expressing transgene that is specifically expressed in GC B cells. Concerted activation of both oncogenes led to increased expansion of GC B cells upon immunization, followed within a few months by the onset of aggressive, invasive B-cell lymphomas. Our progress in characterizing this disease model will be presented at the meeting.