Enhanced expression of p16(ink4a) is associated with a poor prognosis in childhood acute lymphoblastic leukemia

The tumor suppressor gene p16(ink4a) is homozygously deleted in numerous T as well as in some B lineage acute lymphoblastic leukemia (ALL). We therefo re analyzed the clinical and biological implications of this feature by stu dying p16(ink4a) expression in 58 cases of childhood ALL. mRNA and protein were significantly correlated and both appeared more highly expressed in B than in T lineage ALLs: 13 out of the 15 T cell ALLs did not show any p16(i nk4a) expression. The main result of this study is the strong prognostic va lue of p16(ink4a) expression. When stratifying the patients in three groups according to p16(ink4a) expression, we observed in univariate analysis: (1 ) the shortest disease-free survival for patients presenting a high p16(ink 4a) level; (2) contrasting with the good prognosis in the group of patients expressing p16(ink4a) at low level; (3) while cases without any expression of the inhibitor were associated with a medium course of the disease (P = 0.0165). This prognostic value was confirmed by the multivariate analysis s howing therapeutic regimen and p16(ink4a) protein expression as the only va riables retained in the model. A specific metabolic profile related to cell ular survival and proliferation was observed in each of the three p16(ink4a ) expression groups. Among the cell cycle-related proteins we analyzed, onl y p21(waf1) bcl-2 and CDK4 were significantly and positively correlated to p16(ink4a). Furthermore, CDK6 was also strongly expressed in the group of c ases with high p16(ink4a) level. An enhancement of p16(ink4a), p21(waf1) an d bcl-2 was previously described in prolonged cellular survival, while agin g cells showed a decrease in CDK4 expression. The concomitant high expressi on of the oncogenic protein CDK4 (and of CDK6), we observed, may amplify th e leukemic advantage of prolonged lifespan blast cells by favoring cell pro gression through G1 phase. These data suggest that at least two mechanisms may be associated in the oncogenesis of very aggressive ALLs, ie deregulati on of cell multiplication and prolonged blast lifespan.