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 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.
Xu
B
B
Division of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
Grandér
D
D
Sangfelt
O
O
Einhorn
S
S
D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004351:Drug Resistance; D004790:Enzyme Induction; D006801:Humans; D000077190:Interferon alpha-2; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D007700:Kinetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D011994:Recombinant Proteins; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C494227:IRF9 protein, human; D000077190:Interferon alpha-2; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D011994:Recombinant Proteins; D014157:Transcription Factors; D007371:Interferon-gamma; D015088:2',5'-Oligoadenylate Synthetase