Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
26467384
DOI
10.1158/1078-0432.ccr-15-1191
PII: 1078-0432.CCR-15-1191
Knihovny.cz E-zdroje
- MeSH
- apoptóza účinky léků MeSH
- bicyklické sloučeniny heterocyklické aplikace a dávkování MeSH
- bifenylové sloučeniny aplikace a dávkování MeSH
- difúzní velkobuněčný B-lymfom klasifikace farmakoterapie genetika patologie MeSH
- harringtoniny aplikace a dávkování MeSH
- homoharringtonin MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nitrofenoly aplikace a dávkování MeSH
- piperaziny aplikace a dávkování MeSH
- proliferace buněk účinky léků MeSH
- protein bcl-X biosyntéza MeSH
- protein MCL-1 biosyntéza genetika MeSH
- protoonkogenní proteiny c-bcl-2 biosyntéza genetika MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- sulfonamidy aplikace a dávkování MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- ABT-737 MeSH Prohlížeč
- BCL2L1 protein, human MeSH Prohlížeč
- bicyklické sloučeniny heterocyklické MeSH
- bifenylové sloučeniny MeSH
- harringtoniny MeSH
- homoharringtonin MeSH
- MCL1 protein, human MeSH Prohlížeč
- nitrofenoly MeSH
- piperaziny MeSH
- protein bcl-X MeSH
- protein MCL-1 MeSH
- protoonkogenní proteiny c-bcl-2 MeSH
- sulfonamidy MeSH
- venetoclax MeSH Prohlížeč
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
Citace poskytuje Crossref.org
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