title: Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma.
abstract: OBJECTIVE
  To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL).
  
  
  METHODS
  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.
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. First Department of Medicine - Department of Hematology, General University Hospital and Charles University in Prague, Prague, Czech Republic. magdalena.klanova@seznam.cz.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Klanova
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Andera
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Brazina
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Svadlenka
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Czech Republic.
authors.forename: Simona
authors.initials: S
authors.lastname: Benesova
authors.affiliation: Department of Patology and Molecular Medicine, Second Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Soukup
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Prukova
authors.affiliation: First Department of Medicine - Department of Hematology, General University Hospital and Charles University in Prague, Prague, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Vejmelkova
authors.affiliation: Institute of Pathology, General University Hospital, Charles University in Prague, Prague, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Jaksa
authors.affiliation: Faculty of Informatics and Statistics, University of Economics, Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Helman
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. First Department of Medicine - Department of Hematology, General University Hospital and Charles University in Prague, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Vockova
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. First Department of Medicine - Department of Hematology, General University Hospital and Charles University in Prague, Prague, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Lateckova
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. First Department of Medicine - Department of Hematology, General University Hospital and Charles University in Prague, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Molinsky
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Bokang Calvin Lenyeletse
authors.initials: BC
authors.lastname: Maswabi
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Mahmudul
authors.initials: M
authors.lastname: Alam
authors.affiliation: Department of Patology and Molecular Medicine, Second Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.
authors.forename: Roman
authors.initials: R
authors.lastname: Kodet
authors.affiliation: First Department of Medicine - Department of Hematology, General University Hospital and Charles University in Prague, Prague, Czech Republic.
authors.forename: Robert
authors.initials: R
authors.lastname: Pytlik
authors.affiliation: First Department of Medicine - Department of Hematology, General University Hospital and Charles University in Prague, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Trneny
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. First Department of Medicine - Department of Hematology, General University Hospital and Charles University in Prague, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Klener
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006248:Harringtonines / Q000008:administration & dosage; D000077863:Homoharringtonine; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis* / Q000235:genetics; D009596:Nitrophenols / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000096:biosynthesis*
chemical_list: C501332:ABT-737; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006248:Harringtonines; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; D000077863:Homoharringtonine; C579720:venetoclax