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Deoxycytidine kinase expression in AML blasts and its relationship to leukemia-free and overall survival
L. Ng1,, , C. Chan2, T. Au2, C.K. Cheng3, K.F. Mo2, W. Li2, K. Lei2, T. Mok2, M. Ng3, R. Raghupathy2
1 Faculty of Medicine, The Chinese University of Hong Kong (CUHK)
2 Partner State Key Laboratory of Oncology in South China, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, CUHK
3 Blood Cancer Cytogenetics and Genomics Laboratory, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, CUHK, Hong Kong

Aim: Study the correlation of expression of genes involved in cytarabine metabolism to leukemia-free (LFS) and overall survival (OS) in AML.

Introduction: Cytarabine is the backbone of AML therapy. Understanding the roles and polymorphisms of genes involved in cytarabine metabolism and resistance in AML will facilitate development of novel therapeutics.

Methods: Adults less than 60 years with non M3 AML were included. Archived diagnostic marrow samples were studied for expression of 10 genes involved in cytarabine metabolism by RT-qPCR; gene expression normalized to GAPDH was compared using the unpaired t-test with Welch correction. SNP rs4694362 in deoxycytidine kinase (DCK) gene was tested using Taqman assay. Median time to relapse and survival was calculated by Kaplan Meier method.

Results: 21 Han Chinese patients (median age: 50) were identified; 15 were male; 16 had intermediate risk cytogenetics; 5 had a blast count of over 100×109/L at diagnosis. 17 patients achieved CR; 12 after first induction. No difference in gene expression was seen between CR (n=12) versus non CR (n=9) with first induction. 17 CR patients were followed for a median duration of 67.5 months; median time to relapse was 15 months. 1 patient who underwent allogeneic transplant in CR1 was excluded. Higher mean DCK expression was seen in patients with LFS longer than (n=7) versus less than 2 years (n=9) (1.91±0.67, p: 0.01) and in those with OS longer than (n=8) versus less than 3 years (n=8) (2.02±0.69, p: 0.01). DCK rs4694362 TT genotype was less prevalent than CT in patients with >2 year LFS; but not statistically significant. (49% vs 60%, p: 0.6).1,2

Conclusion: DCK phosphorylates cytarabine to its active metabolite. Our work shows that higher DCK expression is correlated to LFS and OS in AML. The role of DCK SNP rs4694362 should be explored further in the Chinese.

J. Cai,V.L. Damaraju,N. Groulx
Two distinct molecular mechanisms underlying cytarabine resistance in human leukemic cells
Cancer Res, 68 (2008), pp. 2349-2357 http://dx.doi.org/10.1158/0008-5472.CAN-07-5528
A. Abraham,S. Varatharajan,S. Karathedath
RNA expression of genes involved in cytarabine metabolism and transport predicts cytarabine response in acute myeloid leukemia
Pharmacogenomics, 16 (2015), pp. 877-890 http://dx.doi.org/10.2217/pgs.15.44

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