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Huntingtin-interacting protein 1-related (HIP1R) is an endocytic protein involved in receptor trafficking, including regulating cell surface expression of receptor tyrosine kinases. We have previously shown that low HIP1R protein expression was associated with poorer survival in diffuse large B-cell lymphoma (DLBCL) patients from Denmark treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). In this multicenter study, we extend these findings and validate the prognostic and subtyping utility of HIP1R expression at both transcript and protein level. Using data mining on three independent transcriptomic datasets of DLBCL, HIP1R transcript was preferentially expressed in germinal center B-cell (GCB)-like DLBCL subtype (Phi/HIP1R lo phenotype) exhibited poorer OS (P=0.0038) and PFS (P=0.0134). Multivariate analysis showed that HIP1Rhi/HIP1R lo subgroup of patients exhibited inferior OS and PFS (P

Background Imatinib mesylate (IM) is the gold standard drug for chronic myeloid leukemia (CML) treatment. However, intrinsic and acquired resistance against IM has become a problem in CML treatment. Vascular endothelial growth factor receptor 2 (VEGFR2) plays a pivotal role in leukemia associated angiogenesis. Its expression is a good predictor of poor survival in CML. Genetic polymorphisms in VEGFR2 result in varied VEGFR2 expression and may lead to inter individual variation in disease progression and outcome to IM therapy. Aim of this study was to investigate the frequencies of VEGFR2 polymorphisms rs1531289 and rs2305948 in Malaysian CML patients and to determine the impact of these SNPs on IM treatment response in these CML patients. Methods DNA extracted from 230 CML patients (121 IM resistant and 109 IM good response) were genotyped using restriction fragment length polymorphism analysis and genotypes were categorized into homozygous wildtype, heterozygous and homozygous variants. The difference in genotype frequencies of the two SNPs, between the two groups of CML patients were compared using x2 test and the association between genotypes and treatment response was assessed using logistic regression analysis and deriving ORs with 95% CI. Results The SNP rs1531289 did not show any significant association with IM resistance. For rs2305948, the heterozygous variant genotype (CT) and variant allele (T) showed significant association with IM resistance (OR, 2.38; CI,1.33-4.25, p = 0.003 and OR,1.48; CI, 1.02-2.14,p=0.039 respectively). Haplotype analysis of the two SNPs did not show any association with treatment response. Conclusion VEGFR2 polymorphism rs2305948 which is associated with cytogenetic response and development of resistance to IM therapy might be a potential prognostic predictor of IM treatment response in CML patients. This study was financially supported by Research University Grant of Universiti Sains Malaysia, 2017.

Background Despite success with imatinib mesylate in patients with chronic myeloid leukaemia (CML), emergence of clinical resistance in 30% of patients treated with imatinib mesylate still remains a problem. Resistance could be due to a heterogenous array of mechanisms. Pharamcogenetic variability as a result of genetic polymorphisms in the imatinib mesylate transporter genes ABCB1 , ABCG2 , ABCC1 , and ABCC2 could be potential determinants of variability in imatinib mesylate disposition and efficacy. This study investigated the association between ten polymorphisms of ABCB1 (1236 T>C, 2677G>T/A, 3435C>T), ABCG2 (34G>A, 421 C>A), ABCC1 (2012G>T, 2168G>A), and ABCC2 (−24C>T, 1249G>A, 3972 C>T) genes and response to imatinib mesylate with the ultimate aim of identifying putative genotypes and haplotypes associated with good response or resistance. Methods Blood samples from 215 patients with CML (107 with a good response to imatinib mesylate and 108 who were resistant to imatinib mesylate) were genotyped for the 10 polymorphisms using PCR-RFLP. After determining the genotype and haplotype frequencies, their association with imatinib mesylate response was determined with odds ratio (OR). Findings Resistance was significantly associated with patients who had homozygous ABCB1 1236CC genotype (OR 2.79, p = 0.01). ABCG2 421AA genotype was associated with a good response (OR 0.29, p = 0.01) while 421CC genotype was associated with imatinib mesylate resistance (OR 1.87, p = 0.02). Haplotypes ABCB1 C 1236 G 2677 C 3435 and ABCC2 T- 24 G 1249 T 3972 were associated with imatinib mesylate resistance ( p = 0.04 and p = 0.03 respectively) while ABCG2 A 34 A 421 haplotype was associated with a good response to imatinib mesylate ( p = 0.03). Interpretation Genetic variation in these imatinib mesylate transporter genes might have consequences on mRNA stability, expression, protein folding degradation, intracellular localisation, substrate binding, and/or transporter kinetics and thus modulate variation in response. Pretreatment genotyping of these SNPs in patients with CML could be useful for predicting imatinib mesylate resistance which may allow the best choice of drug treatment for patients with CML.

Introduction Imatinib mesylate (IM) is the first-line treatment and gold standard for treatment of chronic myeloid leukemia (CML). Pharmacokinetic profile of IM and its active metabolite, N-desmethylimatinib (M1) in CML patients are clinically important. Objectives This study aimed to determine the influence of CYP1A2, CYP3A5 and CYP2C19 polymorphisms on the drug response of IM in Asian CML. We also aimed to determine the pharmacokinetic profile for both IM and M1 in CML patients with prescription 400 mg PO. Methodology A total of 250 healthy volunteers (controls) and 50 CML patients (cases) receiving IM were enrolled in a prospective pharmacogenetic study. CYP1A2, CYP3A5 and CYP2C19 polymorphisms were genotyped in both control and case groups using PCR-RFLP. In the pharmacokinetic study, serum IM and M1 concentrations were measured using the validated ultra-high performance liquid chromatography method on first three CML patients with 400 mg IM PO. The χ2 test was used to correlate CYP1A2, CYP3A5 and CYP2C19 genotypes to good responder and resistant group. Results The genotype frequencies of CYP1A2, CYP3A5 and CYP2C19 SNP will be discussed in Malays, Chinese and Indians. In the pharmacokinetic study, we observed high standard deviation (>20% of mean) in volume of distributions (Vd), clearance (CL) and area under curve (AUC) for both IM and M1. For IM, Vd = 113.32 ± 43.52 l, CL = 5.01 ± 1.19 l h-1 and AUC = 62 953.33 ± 9791.38 ng h l-1, whereas for M1, Vd = 415.27 ± 228.72 l, CL = 4.84 ± 3.85 l h-1 and AUC = 5585.15 ± 2950.42 ng h l-1. This preliminary study suggested a high interindividual pharmacokinetic variability in Malaysian CML patients. M1 concentration during steady state (C0) and its time concentration profile were different as per reported in Caucasian population. It suggested that Asians may have a different IM metabolism profile from Caucasians. Summary In short, the preliminary pharmacokinetic data highlighted the potential differences of metabolism profile between Asian and Caucasian. Future validation in a larger sample size is ongoing.