PRIMARY LEUKEMIA-CELLS RESISTANT TO ALPHA-INTERFERON IN-VITRO ARE DEFECTIVE IN THE ACTIVATION OF THE DNA-BINDING FACTOR INTERFERON-STIMULATED GENE FACTOR-3

Cells from one-third of chronic lymphocytic leukemia (CLL) patients ar e resistant to alpha-interferon (alpha-IFN) as measured by induction o f blast transformation. We have previously shown that all CLL clones e xpress alpha/beta-IFN receptors, but that the resistant cells are defe ctive in the induction of the enzyme 2',5'-oligoadenylate synthetase ( 2',5-A synthetase). Thus, the deficiency in IFN sensitivity is localiz ed somewhere between the interaction of the IFN molecule with its rece ptor and induction of 2',5'-A synthetase. We have now further characte rized the resistance of CLL clones to IFN by investigating whether it is associated with a defect in the activation of IFN-stimulated gene f actor 3 (ISGF3), which is involved in the activation of alpha-IFN-stim ulated genes (ISGs). A defect induction of ISGF3 after alpha-IFN treat ment was found in 4 of 12 CLL patients, There was a dose correlation b etween defective induction of ISGF3 and a lack of enhancement of 2',5' -A synthetase as well as induction of blast transformation. Pretreatme nt with gamma-IFN and mixing experiments with extracts from IFN-sensit ive cells indicate that a lack of the gamma-component of ISGF3 was the reason for defect in activation in 2 of the patients. We conclude tha t a defect in activation of ISGF3 is a possible cause for resistance i n CLL cells to IFN-induced blast transformation in vitro. (C) 1994 by The American Society of Hematology.