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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. © 2004 Wiley‐Liss, Inc.