Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia

Ajay Abraham, Savitha Varatharajan, Salar Abbas, Wei Zhang, Ramachandran V. Shaji, Rayaz Ahmed, Aby Abraham, Biju George, Alok Srivastava, Mammen Chandy, Vikram Mathews, Poonkuzhali Balasubramanian*

*Corresponding author for this work

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Aim: Cytidine deaminase (CDA) irreversibly deaminates cytarabine (Ara-C), a key component of acute myeloid leukemia (AML) induction and consolidation therapy. CDA overexpression results in Ara-C resistance, while decreased expression is associated with toxicity. We evaluated factors influencing variation in CDA mRNA expression in adult AML patients and normal controls, and how they contributed to Ara-C cytotoxicity in AML cells. Materials & methods: CDA mRNA expression in 100 de novo AML patients and 36 normal controls were determined using quantitative reverse-transcriptase PCR. Genetic variants in the CDA gene were screened by direct sequencing. IC 50 of Ara-C was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: CDA RNA expression as well as Ara-C IC 50 showed wide variation in AML samples and normal controls. Fourteen sequence variants were identified, three of which (-33delC, intron 2 TCAT repeat and the 3́untranslated region 816delC variants) showed significant association with RNA expression and the nonsynonymous coding variant 79A>C was associated with Ara-C cytotoxicity. Conclusion: CDA genetic variants explain the variation in RNA expression and may be candidates for individualizing Ara-C therapy.

Original languageEnglish (US)
Pages (from-to)269-282
Number of pages14
JournalPharmacogenomics
Volume13
Issue number3
DOIs
StatePublished - Feb 1 2012

Keywords

  • acute myeloid leukemia
  • cytarabine
  • cytidine deaminase
  • drug resistance
  • polymorphisms

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

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    Abraham, A., Varatharajan, S., Abbas, S., Zhang, W., Shaji, R. V., Ahmed, R., Abraham, A., George, B., Srivastava, A., Chandy, M., Mathews, V., & Balasubramanian, P. (2012). Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia. Pharmacogenomics, 13(3), 269-282. https://doi.org/10.2217/pgs.11.149