title: Abundant anti-apoptotic BCL-2 is a molecular target in leukaemias with t(4;11) translocation.
abstract: Chemotherapy resistance from imbalanced apoptosis regulation may contribute to poor outcome in leukaemias with t(4;11). Anti-apoptotic BCL-2 expression and target modulation were characterized in cell lines with t(4;11) and BCL-2 expression was examined in MLL and non-MLL infant/paediatric leukaemia cases by Western blot analysis and/or real-time polymerase chain reaction. Cytotoxicity of Genasensetrade mark (Oblimersen Sodium, G3139) alone or combined with cytotoxic drugs was assessed by MTT [(3-4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assays of the cell lines, applying pharmacostatistical response surface modelling of drug interactions. Apoptosis and cell cycle were evaluated by flow cytometry in RS4:11 cells. Primary leukaemias and cell lines with t(4;11) expressed abundant BCL2 mRNA and protein. Variable, sometimes substantial BCL2 mRNA was detected in other leukaemia subtypes. G3139 reduced BCL2 mRNA and protein in RS4:11 cells. The most sensitive cell line to single-agent G3139 was RS4:11. Low G3139 concentrations sensitized RS4:11 and MV4-11 cells to select anti-leukaemia cytotoxic drugs. In RS4:11 cells, combining G3139 with doxorubicin (ADR) increased active caspase 3 and TUNEL staining compared to ADR alone, indicating greater apoptosis, and G3139 increased S-phase progression. The abundant BCL-2 affords a molecular target in leukaemias with t(4;11). G3139 exhibits preclinical activity and synergy with select cytotoxic agents in RS4:11 and MV4-11 cells, and these effects occur through apoptosis.
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Blaine W
authors.initials: BW
authors.lastname: Robinson
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Behling
authors.forename: Manish
authors.initials: M
authors.lastname: Gupta
authors.forename: Alena Y
authors.initials: AY
authors.lastname: Zhang
authors.forename: Jonni S
authors.initials: JS
authors.lastname: Moore
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Bantly
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Felix
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D013873:Thionucleotides / Q000494:pharmacology; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013873:Thionucleotides; D004317:Doxorubicin; C408162:oblimersen