In vitro drug resistance and prognostic impact of p16(INK4A)/p15(INK4B) deletions in childhood T-cell acute lymphoblastic leukaemia

p16 gene deletions are present in about 70% of primary paediatric T-cell ac ute 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 wit hin the subgroup of T-lineage ALL. We studied the relationship between p16/ p19(ARF) 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 as say using a panel of drugs and the thymidylate synthase inhibition assay fo r methotrexate. There was a complete overlap of individual LC50 values of p 16 gene homozygously deleted and p16 germ-line cases for most of the nine c lasses 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 moder n multiagent chemotherapy schemes of the Dutch Childhood Leukaemia Study Gr oup 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%, P-log (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.