High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia.
Deficiency of functional deoxycytidine kinase (dCK) is a common characteristic for in vitro resistance to cytarabine (AraC). To investigate whether dCK is also a target for induction of AraC resistance in patients with acute myeloid leukemia (AML), we determined dCK messenger RNA (mRNA) expression in (purified) leukemic blasts and phytohemagglutinin-stimulated T cells (PHA T cells) from patients with chemotherapy-sensitive and chemotherapy-resistant AML. In control samples from healthy donors (PHA T cells and bone marrow), only wild-type dCK complementary DNA (cDNA) was amplified. Also, in (purified) leukemic blasts from patients with sensitive AML, only wild-type dCK cDNAs were observed. These cDNAs coded for active dCK proteins in vitro. However, in 7 of 12 (purified) leukemic blast samples from patients with resistant AML, additional polymerase chain reaction fragments with a deletion of exon 5, exons 3 to 4, exons 3 to 6, or exons 2 to 6 were detected in coexpression with wild-type dCK. Deletion of exons 3 to 6 was also identified in 6 of 12 PHA T cells generated from the patients with resistant AML. The deleted dCK mRNAs were formed by alternative splicing and did code for inactive dCK proteins in vitro. These findings suggest that the presence of inactive, alternatively spliced dCK mRNA transcripts in resistant AML blasts may contribute to the process of AraC resistance in patients with AML. (Blood. 2000;96:1517-1524)
Veuger
M J
MJ
Laboratory of Experimental Hematology, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
Honders
M W
MW
Landegent
J E
JE
Willemze
R
R
Barge
R M
RM
D000208:Acute Disease; D017398:Alternative Splicing; D000818:Animals; D018076:DNA, Complementary / Q000235:genetics; D003842:Deoxycytidine Kinase / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D051381:Rats
D018076:DNA, Complementary; D007527:Isoenzymes; D003842:Deoxycytidine Kinase