Polymorphic Variation at the STAT5 Locus Is Associated with the Response of CML Patients to Interferon Alpha.

Interferon alpha (IFN) induces complete hematologic remission in 70% to 80% of patients with CML in early chronic phase, with up to 8–30% of cases achieving a complete cytogenetic response (CCR). Although patient responses correlate with Hasford and Sokal risk scores, the molecular basis for this heterogeneity remains poorly understood. We hypothesized that polymorphic differences in the IFN signal transduction cascade might account for different patient responses. IFN binds the heterodimeric type I interferon receptor, the two subunits of which are encoded by IFNAR1 and IFNAR2. Binding activates the JAK1 and TYK2 non-receptor tyrosine kinases, which phosphorylate and activate STAT proteins. We studied 187 cases treated with IFN based regimens as part of the German CML studies I-III. Of these, 105 were defined as non-responders (no cytogenetic response) and 82 as responders (achievement of <=34% Philadelphia-chromosome positive metaphases) after a median treatment duration of 23 and 40 months, respectively. There was no significant difference in the incidence of der(9) deletions between the two groups. We genotyped 14 single nucleotide polymorphisms (SNPs) within or close to the genes encoding IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT3 and STAT5a/b and compared allele frequencies between responders and non-responders. Significant differences were found for two SNPs at the STAT5a and STAT5b loci. For rs16967611 the minor allele frequency (maf) was 0.34 for non-responders and 0.28 for responders (P=0.21; chi-squared test) and for rs6503691 the maf was 0.16 for non-responders and 0.07 for responders (P=0.005). The latter SNP remained significant when corrected for multiple testing. Three other SNPs at STAT5a/b (rs9900213, rs17500235 and rs17591972) were also analyzed and yielded P values of 0.87, 0.01 and 0.15 respectively. STAT5a, STAT5b and STAT3 are tightly linked at 17q21 and show strong linkage disequilibrium according to HapMap data. To determine if the genotype at rs6503691 is related to gene expression levels, we measured STAT5a, STAT5b and STAT3 mRNA in 214 pretreatment CML patients by real time quantitative PCR. There was no difference in the median normlised expression of STAT3 and STAT5a in cases with a c/c genotype compared to those with c/t or t/t, however for STAT5b the expression level was higher in cases with a c/c genotype (P=0.02). We conclude that rs6503691, located within STAT5b intron 1, is associated with the expression level of STAT5b and response of CML patients to IFN.