Abstract
Resistance to cytarabine is an important cause of therapy failure in persons with acute myeloid leukemia (AML). Deoxycytidine kinase, encoded by DCK, catalyzes phosphorylation of cytarabine to cytarabine monophosphate, a necessary step for eventual incorporation of cytarabine triphosphate into DNA and for clinical efficacy. Whether DCK mutations make AML cells resistant to cytarabine is controversial. We studied DCK mutations and messenger RNA (mRNA) concentrations in leukemia cells from 10 subjects with AML who received cytarabine-based therapy and relapsed and in 2 artificially induced cytarabine-resistant AML cell lines. DCK mutations were detected in 4 subjects with AML relapsing after achieving a complete remission and receiving high-dose cytarabine postremission therapy. Most mutations were in exons 4–6 and were not present before therapy. DCK was also mutated in cytarabine-resistant but not parental AML cell lines. DCK mRNA concentrations were significantly decreased in cytarabine-resistant K562 and SHI-1 cells compared with cytarabine-sensitive parental cells. Mutation frequency of DCK and mRNA concentration did not correlate with the extent of cytarabine resistance indicating other factors operate. Overexpression of wild-type DCK restored cytarabine sensitivity to previously resistant leukemia cell lines. Our data contribute to the understanding of cytarabine resistance in persons with AML.
Journal Section:
Original Paper
References
1.
Rowe
JM
, Kim
HT
, Cassileth
PA
, Lazarus
HM
, Litzow
MR
, Wiernik
PH
, . Adult patients with acute myeloid leukemia who achieve complete remission after 1 or 2 cycles of induction have a similar prognosis: a report on 1980 patients registered to 6 studies conducted by the Eastern Cooperative Oncology Group
. Cancer
. 2010
;116
(21
):5012
–21
.2.
Cros
E
, Jordheim
L
, Dumontet
C
, Galmarini
CM
. Problems related to resistance to cytarabine in acute myeloid leukemia
. Leuk Lymphoma
. 2004
;45
(6
):1123
–32
.3.
Tallman
MS
, Gilliland
DG
, Rowe
JM
. Drug therapy for acute myeloid leukemia
. Blood
. 2005
;106
(4
):1154
–63
.4.
Rowe
JM
. Optimal induction and post-remission therapy for AML in first remission
. Hematology Am Soc Hematol Educ Program
. 2009
:396
–405
.5.
Yin
B
, Morgan
K
, Hasz
DE
, Mao
Z
, Largaespada
DA
. Nfl gene inactivation in acute myeloid leukemia cells confers cytarabine resistance through MAPK and mTOR pathways
. Leukemia
. 2006
;20
(1
):151
–4
.6.
Yin
B
, Kogan
SC
, Dickins
RA
, Lowe
SW
, Largaespada
DA
. Trp53 loss during in vitro selection contributes to acquired Ara-C resistance in acute myeloid leukemia
. Exp Hematol
. 2006
;34
(5
):631
–41
.7.
Stegmann
AP
, Honders
WH
, Willemze
R
, Ruiz van Haperen
VW
, Landegent
JE
. Transfection of wild-type deoxycytidine kinase (dck) cDNA into an AraC- and DAC-resistant rat leukemic cell line of clonal origin fully restores drug sensitivity
. Blood
. 1995
;85
(5
):1188
–94
.8.
Veuger
MJ
, Honders
MW
, Landegent
JE
, Willemze
R
, Barge
RM
. High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia
. Blood
. 2000
;96
(4
):1517
–24
.9.
Rathe
SK
, Moriarity
BS
, Stoltenberg
CB
, Kurata
M
, Aumann
NK
, Rahrmann
EP
, . Using RNA-seq and targeted nucleases to identify mechanisms of drug resistance in acute myeloid leukemia
. Sci Rep
. 2014
;4
:6048
.10.
van den Heuvel-Eibrink
MM
, Wiemer
EA
, Kuijpers
M
, Pieters
R
, Sonneveld
P
. Absence of mutations in the deoxycytidine kinase (dCK) gene in patients with relapsed and/or refractory acute myeloid leukemia (AML)
. Leukemia
. 2001
;15
(5
):855
–6
.11.
Malani
D
, Murumägi
A
, Yadav
B
, Kontro
M
, Eldfors
S
, Kumar
A
, . Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML
. Leukemia
. 2017
;31
(5
):1187
–95
.12.
Yin
B
, Delwel
R
, Valk
PJ
, Wallace
MR
, Loh
ML
, Shannon
KM
, . A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene
. Blood
. 2009
;113
(5
):1075
–85
.13.
Su
G
, Lian
X
, Tan
D
, Tao
H
, Liu
H
, Chen
S
, . Aberrant expression of ecotropic viral integration site-1 in acute myeloid leukemia and acute lymphoblastic leukemia
. Leuk Lymphoma
. 2015
;56
:472
–9
.14.
Leukemia & Lymphoma Group, Chinese Society of Hematology, Chinese Medical Association
. Chinese guidelines for diagnosis and treatment of adult acute myeloid leukemia (not APL) (2017)
. Zhonghua Xue Ye Xue Za Zhi
. 2017 Mar
;38
:177
–82
.15.
Kobayashi
T
, Kakihara
T
, Uchiyama
M
, Fukuda
T
, Kishi
K
, Shibata
A
. Low expression of the deoxycytidine kinase (dCK) gene in a 1-beta-D-arabinofuranosylcytosine-resistant human leukemic cell line KY-Ra
. Leuk Lymphoma
. 1994
;15
(5–6
):503
–5
.16.
Kakihara
T
, Fukuda
T
, Tanaka
A
, Emura
I
, Kishi
K
, Asami
K
, . Expression of deoxycytidine kinase (dCK) gene in leukemic cells in childhood: decreased expression of dCK gene in relapsed leukemia
. Leuk Lymphoma
. 1998
;31
(3–4
):405
–9
.17.
Rathe
SK
, Largaespada
DA
. Deoxycytidine kinase is downregulated in Ara-C-resistant acute myeloid leukemia murine cell lines
. Leukemia
. 2010
;24
(8
):1513
–5
.18.
Stegmann
AP
, Honders
MW
, Willemze
R
, Landegent
JE
. De novo induced mutations in the deoxycytidine kinase (dck) gene in rat leukemic clonal cell lines confer resistance to cytarabine (AraC) and 5-aza-2′-deoxycytidine (DAC)
. Leukemia
. 1995
;9
(6
):1032
–8
.19.
Shi
JY
, Shi
ZZ
, Zhang
SJ
, Zhu
YM
, Gu
BW
, Li
G
, . Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients
. Pharmacogenetics
. 2004
;14
(11
):759
–68
.20.
Zhang
DY
, Yuan
XQ
, Yan
H
, Cao
S
, Zhang
W
, Li
XL
, . Association between DCK 35708 T>C variation and clinical outcomes of acute myeloid leukemia in South Chinese patients
. Pharmacogenomics
. 2016
;17
(14
):1519
–31
.© 2021 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2021
You do not currently have access to this content.
