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Abstract

The tumor suppressor gene p16 ink4a is homozygously deleted in numerous T as well as in some B lineage acute lymphoblastic leukemia (ALL). We therefore analyzed the clinical and biological implications of this feature by studying 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 ink4a expression. The main result of this study is the strong prognostic value 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 ink4a 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 showing therapeutic regimen and p16 ink4a protein expression as the only variables retained in the model. A specific metabolic profile related to cellular survival and proliferation was observed in each of the three p16 ink4a expression groups. Among the cell cycle-related proteins we analyzed, only p21 waf1 bcl-2 and CDK4 were significantly and positively correlated to p16 ink4a . Furthermore, CDK6 was also strongly expressed in the group of cases with high p16 ink4a level. An enhancement of p16 ink4a , p21 waf1 and bcl-2 was previously described in prolonged cellular survival, while aging cells showed a decrease in CDK4 expression. The concomitant high expression of the oncogenic protein CDK4 (and of CDK6), we observed, may amplify the leukemic advantage of prolonged lifespan blast cells by favoring cell progression through G1 phase. These data suggest that at least two mechanisms may be associated in the oncogenesis of very aggressive ALLs, ie deregulation of cell multiplication and prolonged blast lifespan.