High expression of bfl-1 contributes to the apoptosis resistant phenotype in B-cell chronic lymphocytic leukemia

Int J Cancer. 2005 Feb 20;113(5):730-7. doi: 10.1002/ijc.20614.


In order to identify regulatory genes involved in the development of an apoptosis-resistant phenotype in patients with chemotherapy refractory B-cell chronic lymphocytic leukemia (B-CLL) expression of apoptosis-regulating genes in B-CLL cells was quantified using cDNA arrays and RT-PCR. Data were obtained from and compared between 2 groups of B-CLL patients with either nonprogressive, indolent, previously untreated disease and with leukemic cells sensitive to in vitro fludarabine-induced apoptosis, referred to as sensitive B-CLL (sB-CLL) or with progressive, chemotherapy refractory disease and with leukemic cells resistant to in vitro fludarabine-induced apoptosis, referred to as resistant B-CLL (rB-CLL). By performing a supervised clustering of genes that most strongly discriminated between rB-CLL vs. sB-CLL a small group of genes was identified, where bfl-1 was the strongest discriminating gene (p < 0.05), with higher expression in rB-CLL. A group of apoptosis-regulating genes were modulated during induction of apoptosis by serum deprivation in vitro in a similar manner in all cases studied. However, bfl-1 was preferentially downregulated in sB-CLL as compared to rB-CLL (p < 0.05). We conclude that bfl-1 may be an important regulator of B-CLL apoptosis, which could contribute to disease progression and resistance to chemotherapy, and as such represent a future potential therapeutic target.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects
  • Apoptosis / genetics*
  • Culture Media, Serum-Free / pharmacology
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Leukemic
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Male
  • Middle Aged
  • Minor Histocompatibility Antigens
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Up-Regulation
  • Vidarabine / adverse effects
  • Vidarabine / analogs & derivatives*


  • Antineoplastic Agents
  • BCL2-related protein A1
  • Culture Media, Serum-Free
  • Minor Histocompatibility Antigens
  • Proto-Oncogene Proteins c-bcl-2
  • DNA (Cytosine-5-)-Methyltransferases
  • Vidarabine
  • fludarabine