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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1517-1524
NEOPLASIA
High incidence of alternatively spliced forms of deoxycytidine
kinase in patients with resistant acute myeloid leukemia
Marjan J. T. Veuger,
M.
Willy Honders,
Jim E. Landegent,
Roel Willemze, and
Renée M. Y. Barge
From the Laboratory of Experimental Hematology,
Department of Hematology, Leiden University Medical Center, Leiden, The
Netherlands.
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.
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