Universal inactivation of both p16 and p15 but not downstream components is an essential event in the pathogenesis of T-cell acute lymphoblastic leukemia

Motoko Omura-Minamisawa, Mitchell B. Diccianni, Ayse Batova, Ray C. Chang, Louis J. Bridgeman, John Yu, Jeanette Pullen, W. Paul Bowman, Alice L. Yu

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39 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1219-1228
Number of pages10
JournalClinical Cancer Research
Volume6
Issue number4
StatePublished - Apr 2000

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    Omura-Minamisawa, M., Diccianni, M. B., Batova, A., Chang, R. C., Bridgeman, L. J., Yu, J., Pullen, J., Bowman, W. P., & Yu, A. L. (2000). Universal inactivation of both p16 and p15 but not downstream components is an essential event in the pathogenesis of T-cell acute lymphoblastic leukemia. Clinical Cancer Research, 6(4), 1219-1228.