Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26467384
DOI
10.1158/1078-0432.ccr-15-1191
PII: 1078-0432.CCR-15-1191
Knihovny.cz E-resources
- MeSH
- Apoptosis drug effects MeSH
- Bridged Bicyclo Compounds, Heterocyclic administration & dosage MeSH
- Biphenyl Compounds administration & dosage MeSH
- Lymphoma, Large B-Cell, Diffuse classification drug therapy genetics pathology MeSH
- Harringtonines administration & dosage MeSH
- Homoharringtonine MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Nitrophenols administration & dosage MeSH
- Piperazines administration & dosage MeSH
- Cell Proliferation drug effects MeSH
- bcl-X Protein biosynthesis MeSH
- Myeloid Cell Leukemia Sequence 1 Protein biosynthesis genetics MeSH
- Proto-Oncogene Proteins c-bcl-2 biosynthesis genetics MeSH
- Gene Expression Regulation, Neoplastic drug effects MeSH
- Sulfonamides administration & dosage MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- ABT-737 MeSH Browser
- BCL2L1 protein, human MeSH Browser
- Bridged Bicyclo Compounds, Heterocyclic MeSH
- Biphenyl Compounds MeSH
- Harringtonines MeSH
- Homoharringtonine MeSH
- MCL1 protein, human MeSH Browser
- Nitrophenols MeSH
- Piperazines MeSH
- bcl-X Protein MeSH
- Myeloid Cell Leukemia Sequence 1 Protein MeSH
- Proto-Oncogene Proteins c-bcl-2 MeSH
- Sulfonamides MeSH
- venetoclax MeSH Browser
PURPOSE: To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL). 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.
Faculty of Informatics and Statistics University of Economics Prague Czech Republic
Institute of Molecular Genetics Academy of Sciences of the Czech Republic Czech Republic
Institute of Pathology General University Hospital Charles University Prague Prague Czech Republic
References provided by Crossref.org
BH3 Mimetics in Hematologic Malignancies
BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas
Drug Resistance in Non-Hodgkin Lymphomas
