Expression of interferon regulatory factor (IRF) genes and response to interferon-alpha in chronic myeloid leukaemia.
Interferon regulatory factors (IRF) 1 and 2 are DNA-binding proteins which control interferon (IFN) gene expression. IRF1 functions as an activator for IFN and IFN-inducible genes, whereas IRF2 represses the action of IRF1. Expression of the two regulatory genes is itself IFN-inducible. Because therapeutic responses of chronic myeloid leukaemia (CML) patients to IFN-alpha may be determined by intracellular levels of these two mutually antagonistic transcription factors, we have devised a competitive reverse-transcription polymerase chain reaction (RT-PCR) assay which provides an estimate of the ratio of IRF1 to IRF2 expression in a given cell population. Analysis of peripheral blood leucocytes from 25 normal individuals showed that the IRF1:IRF2 ratio varied between 1.13 and 2.30 (mean +/- s.d. 1.49 +/- 0.33). Similar values were obtained for normal bone marrow specimens, with no significant difference between CD34+ and CD34- cells. In contrast, the IRF1:IRF2 ratio in leucocytes from CML patients showed a much wider variation (0.53-5.11). Eleven out of 130 patients in chronic phase had ratios above the normal range, whereas none of the 33 blast crisis samples had a ratio >2.5. Analysis of diagnostic specimens in 59 CML patients treated subsequently with IFN-alpha showed a high IRF1:IRF2 ratio of 5.11 in one of two patients who became complete responders; all the 53 patients with minimal or no cytogenetic response had ratios below 2.5. In a separate series of 97 CML patients studied after IFN-alpha therapy a highly significant correlation was found between the IRF1:IRF2 ratio and both the cytogenetic and the molecular response (ie low concentration of BCR-ABL transcripts) to treatment: 53 out of 115 prospectively analysed samples of good cytogenetic responders had ratios above 2.0, as opposed to only 13 out of 91 samples from poor responders (P < 0.0001; chi2 test). We conclude that a high ratio of IRF1/IRF2 expression may be associated with good cytogenetic and molecular response to IFN-alpha in CML.
Hochhaus
A
A
LRF Centre for Adult Leukaemia, Department of Haematology, Royal Postgraduate Medical School, London, UK.
Yan
X H
XH
Willer
A
A
Hehlmann
R
R
Gordon
M Y
MY
Goldman
J M
JM
Melo
J V
JV
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D016898:Interferon-alpha / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000628:therapy*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins; D014157:Transcription Factors
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; C494229:IRF2 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D016898:Interferon-alpha; D010750:Phosphoproteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors