Autologous T-cell activation fosters ABT-199 resistance in chronic lymphocytic leukemia: rationale for a combined therapy with SYK inhibitors and anti-CD20 monoclonal antibodies.
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SUBMITTER: Elias EE
PROVIDER: S-EPMC6165796 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
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Autologous T-cell activation fosters ABT-199 resistance in chronic lymphocytic leukemia: rationale for a combined therapy with SYK inhibitors and anti-CD20 monoclonal antibodies.
Elías Esteban Enrique EE Almejún María Belén MB Colado Ana A Cordini Gregorio G Vergara-Rubio Maricef M Podaza Enrique E Risnik Denise D Cabrejo María M Fernández-Grecco Horacio H Bezares Raimundo Fernando RF Custidiano María Del Rosario MDR Sánchez-Ávalos Julio César JC Vicente Ángeles Á Garate Gonzalo Martín GM Borge Mercedes M Giordano Mirta M Gamberale Romina R
Haematologica 20180510 10
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Project description:Background and purposeAlthough the ongoing clinical trials of ABT-263 and ABT-199 in chronic lymphocytic leukaemia (CLL) have indicated that BH3 mimetics hold considerable promise, understanding the mechanism of CLL resistance to BH3 mimetics remains a challenge.Experimental approachThe LD50 values of ABT-737, ABT-263 and ABT-199 in a number of primary CLL cells from 40 patients, were determined. The levels of Bcl-2 family proteins, including phosphorylated Bcl-2 (pBcl-2) and their interactions were measured by immunoblotting and co-immunoprecipitation. In vitro binding assays were performed by isothermal titration calorimetry and ELISA. BH3 profiling in isolated mitochondria was analysed.Key resultsThe ratio of (Mcl-1 + pBcl-2) to Bcl-2 expression provided the most significant predictive marker for the cytotoxic potential of ABT-737, ABT-263 and ABT-199 in the panel of CLL samples. Mechanistically, pBcl-2 inhibited the effects of the ABT compounds on the displacement of Bax and Bim from Bcl-2, thereby suppressing mitochondrial apoptosis. The ABT compounds exhibited 100-300-fold lower binding affinity to the glutamic acid, phosphomimetic, mutant of Bcl-2 (T69E, S70E and S87E; EEE-Bcl-2). BH3 peptides exhibited different rank orders of binding affinities to full-length WT-Bcl-2 and full-length EEE-Bcl-2.Conclusions and implicationsOur study suggested that a structural alteration in the BH3-binding groove was induced by phosphorylation of Bcl-2. Our data also provided a framework to overcome resistance of CLL cells to the ABT compounds by combining pBcl-2 kinase inhibitors with the ABT compounds.
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