The Cell Cycle Inhibitor p16INK4A Sensitizes Lymphoblastic Leukemia Cells to Apoptosis by Physiologic Glucocorticoid Levels

Abstract

The cyclin-dependent kinase inhibitor p16INKA is frequently inactivated in childhood T-cell acute lymphoblastic leukemia. To investigate possible consequences of this genetic alteration for tumor development, we conditionally expressed p16INK4A in the T-cell acute lymphoblastic leukemia line CCRF-CEM, which carries a homozygous deletion of this gene. In agreement with its reported function, p16INK4A expression was associated with hypophosphorylation of the retinoblastoma protein pRB and stable cell cycle arrest in G0/G1, documenting that the pRB/E2F pathway is functional in these cells. Unexpectedly, p16INK4A expression increased the sensitivity threshold for glucocorticoid (GC)-induced apoptosis from therapeutic to physiologic levels. As a possible explanation for this phenomenon, we found that p16INK4A-arrested cells had elevated GC receptor expression associated with enhanced GC-mediated transcriptional activity and increased responsiveness of the GC-regulated cyclin D3 gene. These data are supported by our previous findings that GC receptor levels critically influence GC sensitivity and imply that p16INK4A inactivation, in addition to allowing unrestricted proliferation, represents a mechanism by which lymphoid tumor cells might escape cell death triggered by endogenous GC.