ELEVATED INTRACELLULAR LEVEL OF BASIC FIBROBLAST GROWTH-FACTOR CORRELATES WITH STAGE OF CHRONIC LYMPHOCYTIC-LEUKEMIA AND IS ASSOCIATED WITHRESISTANCE TO FLUDARABINE

Chronic lymphocytic leukemia (CLL) is characterized by delayed senesce nce and slow accumulation of monoclonal, small lymphocytes. Basic fibr oblast growth factor (bFGF) is a pleiotropic cytokine that plays a rol e in hematopoiesis and apoptosis, Elevated bFGF levels have been detec ted in urine from patients with a variety of neoplastic diseases inclu ding various leukemias; however, the cellular source of the bFGF has n ot been determined. In this study, the intracellular bFGF level in lym phocytes of 36 patients with B-CLL and 15 normal donors was determined using an enzyme-linked immunoassay. In cells derived from patients wi th high-risk disease, the median level of intracellular bFGF was 381.5 pg/2 x 10(5) cells, compared with a median of 90.5 pg/2 x 10(5) cells in patients with intermediate disease, In patients with low-risk dise ase, the median bFGF level was 4.9 pg/2 x 10(5) cells, and in normal c ontrols, it was 6.0 pg/2 x 10(5) cells. The difference in the bFGF lev els was significant for the comparison between low- and intermediate-r isk (P = .00119), low- and high-risk (P < .0001), and intermediate- an d high-risk disease (P = .0001). Immunofluorescent stains of periphera l blood mononuclear cells confirmed CLL lymphocytes as a cellular sour ce of bFGF. To evaluate the potential contribution of elevated intrace llular bFGF levels to the phenotype of CLL cells, leukemic cells were cultured in vitro with an apoptotic stimulus (fludarabine). CLL cells with high intracellular levels of bFGF appeared to be more resistant t o fludarabine treatment. The addition of bFGF to fludarabine-treated C LL cells resulted in a delay of apoptosis and prolonged survival. Thes e data suggest that bFGF may contribute to the resistance of CLL cells to an apoptotic stimulus. (C) 1996 by The American Society of Hematol ogy.