The cell cycle inhibitor p16(INK4A) sensitizes lymphoblastic leukemia cells to apoptosis by physiologic glucocorticoid levels

The cyclin-dependent kinase inhibitor p16(INK4A) is frequently inactivated in childhood T-cell acute lymphoblastic leukemia. To investigate possible c onsequences of this: genetic alteration for tumor development, we condition ally expressed p16(INK4A) in the T-cell acute lymphoblastic leukemia line C CRF-CEM, which carries a homozygous deletion of this gene. In agreement wit h its reported function, p16(INK4A) expression was associated with hypophos phorylation of the retinoblastoma protein pRB and stable cell cycle arrest in G(0)/G(1), documenting that the pRRB/E2F pathway is functional in these cells. Unexpectedly, p16(INK4A) expression increased the sensitivity thresh old for glucocorticoid (GC)-induced apoptosis from therapeutic to physiolog ic levels. As a possible explanation for this phenomenon, we found that p16 (INK4A)-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 previou s findings that GC receptor levels critically influence GC sensitivity and imply that p16(INK4A) inactivation, in addition to allowing unrestricted pr oliferation, represents a mechanism by which lymphoid tumor cells might esc ape cell death triggered by endogenous GC.