In vitro drug resistance and prognostic impact of p16INK4A/P15INK4B deletions in childhood T-cell acute lymphoblastic leukaemia.
p16 gene deletions are present in about 70% of primary paediatric T-cell acute lymphoblastic leukaemia (T-ALL) and 20% of common/precursor B-cell ALL cases. It is not clear what the impact of the frequent p16 deletions is within the subgroup of T-lineage ALL. We studied the relationship between p16/p19ARF deletions, using fluorescence in situ hybridization, and in vitro drug resistance and prognosis in childhood T-ALL at diagnosis. The cellular drug resistance was measured with the methyl thiazol tetrazoliumbromide assay using a panel of drugs and the thymidylate synthase inhibition assay for methotrexate. There was a complete overlap of individual LC50 values of p16 gene homozygously deleted and p16 germ-line cases for most of the nine classes of drugs tested. The only difference was for dexamethasone: the p16-deleted group was more sensitive than the germ-line p16 group (P = 0.030). The homozygously deleted p16 T-ALL patients (n = 34) treated with the modern multiagent chemotherapy schemes of the Dutch Childhood Leukaemia Study Group ALL-VII/-VIII or Co-operative ALL-92/-97 protocols have a significantly lower 5-year disease-free survival (DFS) than germ-line p16 T-ALL (n = 25) (65.1 +/- 9.1% vs. 95.5 +/- 4.4%, Plog rank = 0.021). Hence, this study identifies a subpopulation of primary childhood T-ALL that appears to have an extremely high DFS. However, the observed differences in outcome do not seem to be related to intrinsic resistance for the tested drugs.
Ramakers-van Woerden
N L
NL
University Hospital Vrije Universiteit, Department of Paediatric Haematology/Oncology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. ramakersvanwoerden@azvu.nl
Pieters
R
R
Slater
R M
RM
Loonen
A H
AH
Beverloo
H B
HB
van Drunen
E
E
Heyman
M
M
Moreno
T C
TC
Rots
M G
MG
van Wering
E R
ER
Kamps
W A
WA
Janka-Schaub
G E
GE
Veerman
A J
AJ
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone; D018572:Disease-Free Survival; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D019942:Genes, p16; D005938:Glucocorticoids; D006720:Homozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D008297:Male; D011239:Prednisolone; D012189:Retrospective Studies
D005938:Glucocorticoids; D003907:Dexamethasone; D011239:Prednisolone