Enhanced expression of p16ink4a is associated with a poor prognosis in childhood acute lymphoblastic leukemia

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.

Chromosome 9p21 gene copy number and prognostic significance of p16 in ESFT

“…This is unexpected as one might predict that reduced levels of p16 would result in deregulated activation of cyclindependent kinase 4/6 resulting in uncontrolled cell-cycle transition through the Rb pathway, leading to a higher tumour growth rate. However, high levels of p16 mRNA expression have been related to a shorter event-free survival in acute lymphoid leukaemia (Mekki et al, 1999), breast cancer (Hui et al, 2000) and neuroblastoma (Omura-Minamisawa et al, 2001), and loss of p16 protein expression has previously been associated with the presence of metastatic disease at diagnosis in primary ESFT (P ¼ 0.026, n ¼ 20; Maitra et al, 2001). Interestingly, we found no correlation between p16 protein expression and outcome.…”

Prognostic significance of p16INK4a immunocytochemistry in adult ALL with standard risk karyotype

“…1,3,4,6,11,12 Flow cytometry is an extremely sensitive technique, but the need for prior permeabilization to study p16 INK4a can induce substantial morphological changes in leukemic blasts. Immunocytochemistry technique allows direct identification of leukemic cells leading to easier interpretation.…”

“…However, it has been also reported that enhanced expression of p16 INK4a gene was associated with poor prognosis in childhood ALL. 3 The high level of p16 INK4a expression group was associated with high proliferation rate and enhanced cellular survival. We also observed in our study, in some patients with unfavorable karyotype, a high proportion of leukemic cells expressing the p16 INK4a protein, but the difference was not statistically significant.…”

“…2 p16 INK4a protein expression has also been investigated with various results. Mekki et al 3 observed that enhanced expression of p16 INK4a protein was associated with poor prognosis in childhood ALL. In the CALGB study survival and remission duration did not differ between patients with or without p16 INK4a inactivation.…”

Régulation de p16INK4a, senescence et oncogenèse

“…Par ailleurs, le promoteur et l'exon 1 de INK4a présentent un îlot CpG [6] qui recouvre un certain nombre de ces sites consensus ( Figure 1B) ; sa méthy-lation, anormale, induit l'extinction du gène. Bien qu'une régulation post-transcriptionnelle de INK4a ait été décrite [20], l'analyse conjointe de l'ARNm et de la protéine montre que c'est essentiellement au niveau transcriptionnel qu'intervient sa régulation [11,12,21] : l'étude de la transcription d'INK4a devrait donc permettre de déterminer les facteurs impliqués dans sa régulation, et donc dans la sénescence cellulaire, facteurs dont le dérèglement serait à l'origine du développement de tumeurs.…”