Interferon-stimulated genes in interferon-sensitive and -resistant chronic myelogenous leukemia patients.
alpha-Interferon induces hematological and cytogenetic remissions in some individuals with newly diagnosed Philadelphia-positive chronic myelogenous leukemia. However, interferon-resistant disease occurs in a consistent patient subset (primary resistance) and develops during therapy in additional patients (secondary resistance). Several alpha-interferon-inducible genes have been characterized. In interferon-resistant cell line variants, defects in these genes have been implicated in the mechanisms mediating resistance. We have, therefore, evaluated mRNA expression of four interferon-stimulated genes (ISGs) following alpha-interferon therapy. Twenty-seven chronic myelogenous leukemia patients (ten interferon-sensitive patients, 17 interferon-resistant patients) were studied. Peripheral blood samples were collected prior to and 1 to 7 days after starting interferon therapy and analyzed for the expression of 2'-5' oligoadenylate synthetase, ISG-15, ISG-54, and 6-16 transcripts. Following therapy with alpha-interferon, 2'-5' oligoadenylate synthetase, ISG-54, and 6-16 transcripts were discerned in all patients regardless of their response to interferon. The ISG-15 message was detected in eight of nine interferon-sensitive and in 15 of 16 interferon-resistant patients, as well. Overall, no consistent defect in the ISG system could be identified. Therefore, lack of induction of these genes cannot explain resistance to alpha-interferon in chronic myelogenous leukemia patients. Other mechanisms such as posttranslational modification, leading to defects in the ISG corresponding proteins, may play a role in the development of resistance.
Talpaz
M
M
Department of Clinical Immunology and Biological Therapy, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Chernajovsky
Y
Y
Troutman-Worden
K
K
Wetzler
M
M
Kantarjian
H
H
Gutterman
J U
JU
Kurzrock
R
R
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism*; D015152:Blotting, Northern; D004351:Drug Resistance / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000628:therapy; D012333:RNA, Messenger / Q000032:analysis*; D012334:RNA, Neoplasm / Q000032:analysis*
D016898:Interferon-alpha; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D015088:2',5'-Oligoadenylate Synthetase