The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment.

Tyrosine kinase inhibitor (TKI) therapy results in excellent responses in the majority of patients with chronic myeloid leukaemia. First-line imatinib treatment, with selective switching to nilotinib when patients fail to meet specific molecular targets or for imatinib intolerance, results in excellent overall molecular responses and survival. However, this strategy is less effective in cases of primary imatinib resistance; moreover, 25% of patients develop secondary resistance such that 20-35% of patients initially treated with imatinib will eventually experience treatment failure. Early identification of these patients is of high clinical relevance. Since the drug efflux transporter ABCB1 has previously been implicated in TKI resistance, we determined if early increases in ABCB1 mRNA expression (fold change from diagnosis to day 22 of imatinib therapy) predict for patient response. Indeed, patients exhibiting a high fold rise (⩾2.2, n=79) were significantly less likely to achieve early molecular response (BCR-ABL1IS ⩽10% at 3 months; P=0.001), major molecular response (P<0.0001) and MR4.5 (P<0.0001). Additionally, patients demonstrated increased levels of ABCB1 mRNA before the development of mutations and/or progression to blast crisis. Patients with high fold rise in ABCB1 mRNA were also less likely to achieve major molecular response when switched to nilotinib therapy (49% vs 82% of patients with low fold rise). We conclude that early evaluation of the fold change in ABCB1 mRNA expression may identify patients likely to be resistant to first- and second-generation TKIs and who may be candidates for alternative therapy.

The effect of genetic variants in SERPING1 on the risk of neovascular age-related macular degeneration.

PURPOSE: Genetic factors influence an individual's risk for developing age-related macular degeneration (AMD), a leading cause of irreversible vision loss. Previous studies investigating the potential association between all AMD subtypes and the SERPING1 gene, which encodes a key regulator of the classic complement pathway, have yielded conflicting results. The purpose of this study is to determine whether variations in SERPING1 are associated with neovascular AMD. METHODS: A total of 556 patients with neovascular AMD and 256 ethnically matched controls were genotyped for polymorphisms in SERPING1. A tagging single nucleotide polymorphism (tSNP) approach was used to cover the SERPING1 gene plus 2 kb on each side, spanning the promoter and the 3' untranslated regions. Ten SNPs with a minor allele frequency of 0.10 were covered by three tSNPs (rs1005510, rs11603020, rs2511989). RESULTS: SERPING1 SNPs rs1005510 and rs2511989 were significantly associated with neovascular AMD in our cohort, with rs1005510 conferring an adverse risk effect (OR 1.49, 95% CI 1.18 to 1.88) and rs2511989 conferring a protective effect (OR 0.73, 95% CI 0.59 to 0.90). For both tSNPs, logistic regression of individual genotypes demonstrated statistically significant stepwise changes in the risk of developing AMD. Combined analysis of rs1005510 with variants in CFH and HTRA1 confirmed an independent risk effect. The rs11603020 variant had no effect on AMD susceptibility in this study (OR 0.98, 95% CI 0.78 to 1.24). CONCLUSIONS: The SERPING1 gene is comprehensively investigated in this study (using three tSNPs), and its genetic variants are evaluated in the largest neovascular AMD cohort to date. The hypothesis that SERPING1 has a modest effect on the risk of neovascular AMD is supported by our results.