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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3352-3360
NEOPLASIA
Cellular drug resistance in childhood acute myeloid leukemia
is related to chromosomal abnormalities
Christian M. Zwaan,
Gertjan J. L. Kaspers,
Rob Pieters,
Karel Hählen,
Dieuwke R. Huismans,
Martin Zimmermann,
Jochen Harbott,
Rosalyn M. Slater,
Ursala Creutzig, and
Anjo J. P. Veerman
From the Department of Pediatric Hematology/Oncology,
VU University Medical Center, Amsterdam, The Netherlands;
Department of Oncology/Hematology, Sophia Children's
Hospital/University Hospital Rotterdam, The Netherlands; Dutch
Childhood Leukemia Study Group, The Hague, The Netherlands; AML-BFM
Study Group, University Children's Hospital Münster, Germany;
Oncogenetic Laboratory, Children's Hospital, Giessen,
Germany; Dutch Working Party on Cancer Genetics and
Cytogenetics, The Netherlands; and Department of Clinical
Genetics and Department of Cell Biology and Genetics, Erasmus
University, Rotterdam, The Netherlands.
Specific cytogenetic abnormalities predict prognosis in childhood
acute myeloid leukemia (AML). However, it is unknown why they are
predictive and whether this is related to drug resistance. We
previously reported that Down syndrome (DS) AML was associated with
favorable resistance profiles. Here, we successfully analyzed drug
resistance and (cyto-) genetic abnormalities of 109 untreated childhood
AML samples using the 4-day total cell-kill methyl-thiazol tetrazolium
(MTT) assay. Patients were classified according to the genetic
abnormalities in the leukemic cells: t(8;21), inv(16), t(15;17),
t(9;11), other 11q23 translocations, abnormalities of chromosome 5/7,
trisomy 8 alone, normal karyotype, single random, and multiple (defined
as 2 or more) abnormalities. The DS AML samples were excluded from the
subgroup analysis. Samples with chromosome 5/7 abnormalities were
median 3.9-fold (P = .01) more resistant to cytarabine
than other AML samples. The t(9;11) samples were more sensitive to
cytarabine (median 2.9-fold, P = .002), etoposide
(13.1-fold, P = .001), the anthracyclines (2.9- to
8.0-fold, P < .01), and 2-chlorodeoxyadenosine
(10.0-fold, P = .002) than other AML samples. The trisomy
8 and t(15;17) groups were too small for meaningful analysis. All other
genetic subgroups did not show specific resistance profiles. Overall,
we found no differences in drug resistance in samples taken at
diagnosis between patients remaining in continuous complete remission
(CCR) versus the refractory/relapsed patients. Within several genetic
subgroups, however, relapsed/refractory patients were more cytarabine
resistant when compared with patients remaining in CCR, but numbers
were small and the results were not significant. We conclude that some,
but not all, cytogenetic subgroups in childhood AML display specific
drug-resistance profiles.
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