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.
University Hospital Vrije Universiteit, Department of Paediatric Haematology/Oncology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. ramakersvanwoerden@azvu.nl
N L
NL
Ramakers-van Woerden
R
R
Pieters
R M
RM
Slater
A H
AH
Loonen
H B
HB
Beverloo
E
E
van Drunen
M
M
Heyman
T C
TC
Moreno
M G
MG
Rots
E R
ER
van Wering
W A
WA
Kamps
G E
GE
Janka-Schaub
A J
AJ
Veerman
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