High expression of bfl-1 contributes to the apoptosis resistant phenotype in B-cell chronic lymphocytic leukemia.
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.
Morales
Alejo A
AA
Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden.
Olsson
Anna
A
Celsing
Fredrik
F
Osterborg
Anders
A
Jondal
Mikael
M
Osorio
Lyda M
LM
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects; D017209:Apoptosis / Q000235:genetics*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014740:Vidarabine / Q000009:adverse effects / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; D016895:Culture Media, Serum-Free; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D004248:DNA (Cytosine-5-)-Methyltransferases; D014740:Vidarabine; C024352:fludarabine