Abundant anti-apoptotic BCL-2 is a molecular target in leukaemias with t(4;11) translocation

Blaine W. Robinson, Kathryn C. Behling, Manish Gupta, Alena Y. Zhang, Jonni S. Moore, Andrew D. Bantly, Cheryl L. Willman, Andrew J. Carroll, Peter C. Adamson, Jeffrey S. Barrett, Carolyn A. Felix

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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 Genasense™ (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.

Original languageEnglish (US)
Pages (from-to)827-839
Number of pages13
JournalBritish Journal of Haematology
Volume141
Issue number6
DOIs
StatePublished - Jun 2008

All Science Journal Classification (ASJC) codes

  • Hematology

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