The cell cycle inhibitor p16(INK4A) sensitizes lymphoblastic leukemia cells to apoptosis by physiologic glucocorticoid levels (vol 276, pg 10984, 2001)

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 conditiona lly expressed p16(INK4A) in the T-cell acute lymphoblastic leukemia line CC RF-CEM, which carries a homozygous deletion of this gene. In agreement with its reported function, p16(INK4A) expression was associated with hypophosp horylation of the retinoblastoma protein PRE and stable cell cycle arrest i n G(0)/G(1), documenting that the pRB/E2F pathway is functional in these ce lls. Unexpectedly, p16(INK4A) expression increased the sensitivity threshol d for glucocorticoid (GC)-induced apoptosis from therapeutic to physiologic levels. As a possible explanation for this phenomenon, we found that p16(I NK4A)-arrested cells had elevated GC receptor expression associated with en hanced CC-mediated transcriptional activity and increased responsiveness of the CC-regulated cyclin D3 gene. These data are supported by our previous findings that GC receptor levels critically influence GC sensitivity and im ply that p16(INK4A) inactivation, in addition to allowing unrestricted prol iferation, represents a mechanism by which lymphoid tumor cells might escap e cell death triggered by endogenous GC.