Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma

0456948 - ÚMG 2018 RIV US eng J - Článek v odborném periodiku
Klanova, M. - Anděra, Ladislav - Bražina, Jan - Švadlenka, Jan - Benešová, Simona - Soukup, J. - Průková, D. - Vejmelkova, D. - Jaksa, R. - Helman, K. - Vockova, P. - Lateckova, L. - Molinsky, J. - Maswabi, B.C. - Alam, M. - Kodet, R. - Pytlik, R. - Trneny, M. - Klener, P.
Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma.
Clinical Cancer Research. Roč. 22, č. 5 (2016), s. 1138-1149. ISSN 1078-0432. E-ISSN 1557-3265
Grant CEP: GA ČR GA14-19590S
Institucionální podpora: RVO:68378050
Klíčová slova: NON-HODGKINS-LYMPHOMA * PROGNOSTIC-SIGNIFICANCE * OMACETAXINE MEPESUCCINATE * GENE-EXPRESSION * APOPTOSIS * REARRANGEMENT * SURVIVAL * LEUKEMIA * CANCER * AGENTS
Obor OECD: Genetics and heredity (medical genetics to be 3)
Impakt faktor: 9.619, rok: 2016

Experimental designs: Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, in vitro and in vivo on primary cell-based murine xenograft models of DLBCL.

Results: By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed in vivo using primary cell-based murine xenograft models of DLBCL.

Conclusions: As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL. Clin Cancer Res. 22(5), 1138-49. (C) 2015 AACR.
Trvalý link: http://hdl.handle.net/11104/0257451