EXPRESSION OF INTERFERON REGULATORY FACTOR (IRF) GENES AND RESPONSE TO INTERFERON-ALPHA IN CHRONIC MYELOID-LEUKEMIA

Interferon regulatory factors (IRF) 1 and 2 are DNA-binding proteins w hich control interferon (IFN) gene expression. IRF1 functions as an ac tivator for IFN and IFN-inducible genes, whereas IRF2 represses the ac tion of IRF1. Expression of the two regulatory genes is itself IFN-ind ucible. Because therapeutic responses of chronic myeloid leukaemia (CM L) 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 expres sion in a given cell population. Analysis of peripheral blood leucocyt es from 25 normal individuals showed that the IRF1:IRF2 ratio varied b etween 1.13 and 2.30 (mean +/- s.d. 1.49 +/- 0.33). Similar values wer e obtained for normal bone marrow specimens, with no significant diffe rence between CD34(+) and CD34(-) cells. In contrast, the IRF1:IRF2 ra tio in leucocytes from CML patients showed a much wider variation (0.5 3-5.11). Eleven out of 130 patients in chronic phase had ratios above the normal range, whereas none of the 33 blast crisis samples had a ra tio >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 o ne of two patients who became complete responders; all the 53 patients with minimal or no cytogenetic response had ratios below 2.5. In a se parate series of 97 CML patients studied after IFN-alpha therapy a hig hly significant correlation was found between the IRF1:IRF2 ratio and both the cytogenetic and the molecular response tie low concentration of BCR-ABL transcripts) to treatment: 53 out of 115 prospectively anal ysed samples of good cytogenetic responders had ratios above 2.0, as o pposed to only 13 out of 91 samples from poor responders (P < 0.0001; chi(2) test). We conclude that a high ratio of IRF1/IRF2 expression ma y be associated with good cytogenetic and molecular response to IFN-al pha in CML.