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Primary leukemia cells resistant to alpha-interferon in vitro are defective
in the activation of the DNA-binding factor interferon- stimulated gene
factor 3
B Xu, D Grander, O Sangfelt and S Einhorn
Division of Experimental Oncology, Radiumhemmet, Karolinska Hospital,
Stockholm, Sweden.
Cells from one-third of chronic lymphocytic leukemia (CLL) patients are
resistant to alpha-interferon (alpha-IFN) as measured by induction of blast
transformation. We have previously shown that all CLL clones express
alpha/beta-IFN receptors, but that the resistant cells are defective in the
induction of the enzyme 2',5'-oligoadenylate synthetase (2',5-A
synthetase). Thus, the deficiency in IFN sensitivity is localized somewhere
between the interaction of the IFN molecule with its receptor and induction
of 2',5'-A synthetase. We have now further characterized the resistance of
CLL clones to IFN by investigating whether it is associated with a defect
in the activation of IFN- stimulated gene factor 3 (ISGF3), which is
involved in the activation of alpha-IFN-stimulated genes (ISGs). A defect
induction of ISGF3 after alpha-IFN treatment was found in 4 of 12 CLL
patients. There was a close correlation between defective induction of
ISGF3 and a lack of enhancement of 2',5'-A synthetase as well as induction
of blast transformation. Pretreatment with gamma-IFN and mixing experiments
with extracts from IFN-sensitive 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 that a defect in activation of ISGF3 is a possible
cause for resistance in CLL cells to IFN-induced blast transformation in
vitro.
Volume 84,
Issue 6,
pp. 1942-1949,
09/15/1994
Copyright © 1994 by The American Society of Hematology
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