Double-hit lymphoma (DHL) is a rare subtype of B-cell lymphoma characterized by MYC and either BCL2 or BCL6 chromosomal rearrangements. DHL cases may have different morphology and are included in the updated 2016 WHO classification as a new category of high grade B-cell lymphoma with rearrangements. DHL patients usually undergo a rapidly progressing clinical course and are poorly responsive to standard chemo-immunotherapy. As a consequence, the prognosis of this entity is particularly poor with a median overall survival of approximately one year. ABT-199 (venetoclax) is a potent and selective small-molecule antagonist of BCL-2 recently approved for the treatment of some lymphoid malignancies. In this study, we demonstrate that single-agent ABT-199 efficiently displaces pro-apoptotic BAX from BCL-2 complexes but fails to maintain a significant antitumor activity over time in most MYC+/BCL2+ DHL cell lines and primary cultures, as well as in a xenograft mouse model of DHL. We further identify the accumulation of the BCL2-like protein, BFL-1, to be a major mechanism involved in acquired resistance to ABT-199. We show this phenomenon to be manageable by the BET bromodomain inhibitor CPI203, since gene expression profiling identifies BCL2A1 as one of the top apoptosis-related gene modulated by the compound. Upon CPI203 treatment, simultaneous downregulation of MYC and BFL-1 at both mRNA and protein levels further overcomes resistance to ABT-199 both in vitro and in vivo, allowing DHL cultures and tumor xenografts to undergo synergistic caspase-mediated apoptosis. Together, these findings highlight the relevance of BFL-1 in DHL-associated drug resistance and support the combined use of BCL-2 antagonist and BET inhibitor as a promising therapeutic strategy in patients with aggressive DHL. Citation Format: Anna Esteve-Arenys, Juan Garcia-Valero, David Gonzalez, Aránzazu Chamorro-Jorganes, Vanina Rodriguez, Ivan Dlouhy, Itziar Salaverria, Elias Campo, Dolors Colomer, Antonio Martinez, Grzegorz Rymkiewicz, Patricia Pérez-Galán, Armando Lopez-Guillermo, Gaël Roué. Pharmacological downregulation of BFL-1 by the BET bromodomain inhibitor CPI203 overcomes ABT-199 resistance in MYC+/BCL2+ double hit lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2161. doi:10.1158/1538-7445.AM2017-2161
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