This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Omura-Minamisawa, M. Articles by Yu, A. L. Search for Related Content PubMed PubMed Citation Articles by Omura-Minamisawa, M. Articles by Yu, A. L.

Universal Inactivation of Both p16 and p15 but not Downstream Components Is an Essential Event in the Pathogenesis of T-Cell Acute Lymphoblastic Leukemia¹

Department of Pediatrics/Hematology-Oncology, University of California, San Diego, California 92103 [M. O-M., M. B. D., A. B., R. C. C., L. J. B., A. L. Y.]; The Scripps Research Institute, San Diego, California 92037 [J. Y.]; The University of Mississippi, Jackson, Mississippi 39216 [J. P.]; and Cook Children’s Medical Center, Fort Worth, Texas 76104 [W. P. B.]

p16/p15 regulate the cell cycle pathway by inhibiting the cyclin Ds-CDK4/6 mediated phosphorylation of pRb. We reported previously that in T-cell acute lymphoblastic leukemia (T-ALL), p16 and p15 were frequently (70%) inactivated at the DNA level by deletion, mutation, or hypermethylation. Therefore, we hypothesize that inactivation of the cell cycle regulatory pathway may be essential in the pathogenesis of T-ALL, and that the remaining T-ALL with a wild-type p16/p15 gene likely harbor inactivation of these genes at RNA or protein levels. Alternatively, the downstream components of the pathway including CDK4/6, cyclin Ds, and pRb may be deregulated. In 124 primary T-ALLs, we found inactivation of the p16 and p15 genes at the DNA level in 79 (64%) and 64 (52%) samples, respectively. Only 9 of the 45 samples with wild-type p16 expressed p16 protein, whereas the remaining 36 lacked p16 expression at the RNA or protein level. In the 60 samples with an intact p15 gene, only 2 expressed p15 mRNA, and the only one analyzed lacked p15 protein. Overall, the abrogation rates for p16 and p15 at DNA/RNA/protein levels were 93% (115 of 124) and 99% (123 of 124), respectively. Although no alterations were evident in cyclin Ds or CDK4/6, pRb was hyperphosphorylated in the majority of samples investigated. These findings strongly support that both p16 and p15 are specific targets in the deregulation of the cell cycle pathway in T-ALL and that the inactivation of these genes is most likely essential in the pathogenesis of this disease.

This article has been cited by other articles:

				J.-Y. Koo, I. Sohn, S. Kim, and J. W. Lee Structured polychotomous machine diagnosis of multiple cancer types using gene expression Bioinformatics, April 15, 2006; 22(8): 950 - 958. [Abstract] [Full Text] [PDF]

				C.-H. Pui, M. V. Relling, and J. R. Downing Acute Lymphoblastic Leukemia N. Engl. J. Med., April 8, 2004; 350(15): 1535 - 1548. [Full Text] [PDF]

				J. H. Dalle, M. Fournier, B. Nelken, F. Mazingue, J.-L. Lai, F. Bauters, P. Fenaux, and B. Quesnel p16INK4a immunocytochemical analysis is an independent prognostic factor in childhood acute lymphoblastic leukemia Blood, April 1, 2002; 99(7): 2620 - 2623. [Abstract] [Full Text] [PDF]

				M. Omura-Minamisawa, M. B. Diccianni, A. Batova, R. C. Chang, L. J. Bridgeman, J. Yu, Esther de Wit, F. H. Kung, J. D. Pullen, and A. L. Yu In Vitro Sensitivity of T-Cell Lymphoblastic Leukemia to UCN-01 (7-Hydroxystaurosporine) Is Dependent on p16 Protein Status: A Pediatric Oncology Group Study Cancer Res., December 1, 2000; 60(23): 6573 - 6576. [Abstract] [Full Text]