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

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 acut e lymphoblastic leukemia (T-ALL), p16 and p15 were frequently (similar to 7 0%) 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 remaini ng 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 12 4 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 sam ples with wild-type pld expressed p16 protein, whereas the remaining 36 lac ked p16 expression at the RNA or protein level, In the 60 samples with an i ntact 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/prot ein levels were 93% (115 of 124) and 99% (123 of 124), respectively. Althou gh no alterations were evident in cyclin Ds or CDK4/6, pRb was hyperphospho rylated in the majority of samples investigated. These findings strongly su pport 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 mo st likely essential in the pathogenesis of this disease.