title: A polymorphism associated with STAT3 expression and response of chronic myeloid leukemia to interferon α.
abstract: Interferon alpha (IFN) induces variable responses in chronic myeloid leukemia (CML), with 8-30% of early chronic phase cases achieving a complete cytogenetic response. We hypothesized that polymorphic differences in genes encoding IFN signal transduction components might account for different patient responses. We studied 174 IFN-treated patients, of whom 79 achieved less than 35% Philadelphia-chromosome (Ph) positive metaphases (responders) and 95 failed to show any cytogenetic response (more than 95% Ph-positive metaphases; non-responders). We compared 17 single nucleotide polymorphisms (SNPs) at IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT3 and STAT5a/b between the two groups and found a significant difference for rs6503691, a SNP tightly linked to STAT5a, STAT5b and STAT3 (minor allele frequency 0.16 for non-responders; 0.06 for responders, P=0.007). Levels of STAT3 mRNA correlated with rs6503691 genotype (P<0.001) as assessed by real time quantitative PCR and therefore we conclude that rs6503691 is associated with the STAT3 expression levels and response of CML patients to IFN.
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kreil
authors.forename: Katherine
authors.initials: K
authors.lastname: Waghorn
authors.forename: Thomas
authors.initials: T
authors.lastname: Ernst
authors.forename: Andrew
authors.initials: A
authors.lastname: Chase
authors.forename: Helen
authors.initials: H
authors.lastname: White
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Hehlmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
chemical_list: D016898:Interferon-alpha; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human