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


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. IC₅₀ 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 IC₅₀ showed wide variation in AML samples and normal controls. Fourteen sequence variants were identified, three of which (-33delC, intron 2 TCAT repeat and the 3´untranslated region 816delC variants) showed significant association with RNA expression and the nonsynonymous coding variant 79A>C was associated with Ara-C cytotoxicity.


CONCLUSIONS
CDA genetic variants explain the variation in RNA expression and may be candidates for individualizing Ara-C therapy.
Christian Medical College, Vellore 632004, India.
Ajay
A
Abraham
Savitha
S
Varatharajan
Salar
S
Abbas
Wei
W
Zhang
Ramachandran V
RV
Shaji
Rayaz
R
Ahmed
Aby
A
Abraham
Biju
B
George
Alok
A
Srivastava
Mammen
M
Chandy
Vikram
V
Mathews
Poonkuzhali
P
Balasubramanian
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000627:therapeutic use*; D003564:Cytidine Deaminase / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D007438:Introns; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D020298:U937 Cells; D055815:Young Adult
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D012333:RNA, Messenger; D003561:Cytarabine; D003564:Cytidine Deaminase