Bcl-2, cell cycle regulatory proteins and corticosensitivity in childhood acute lymphoblastic leukaemia.

The results of treatment in childhood acute lymphoblastic leukemia (ALL) remain incompletely satisfactory because of relapses observed even with high dose chemotherapy. The aim of this study was to evaluate the role of bcl-2 or cell cycle regulatory protein expression in peripheral blood cells before and during the first 48 hours of corticotherapy, and corticosensitivity criteria for predicting relapse and prognosis. Fifty two children presenting with ALL were studied at diagnosis and during the first 48 hours of treatment for the level of cell proliferation by measurement of DNA content, and for expression of several cell proliferation regulatory proteins by Western blot. Two criteria for corticosensitivity were used: 1--the number of blast cells present after seven days of treatment with a threshold at 1 G/L (usual criterion), 2--the D8/D1 blast cell ratio, which is independent of the initial leucocytosis. Relapse in the total patient population or in B-cell ALL could only be predicted by the level of leucocytosis before treatment or by p27kip1 expression during the first 48 hours of treatment. Disease free survival was significantly longer when the D8/D1 blast cell ratio was under the 0.75 quartile in the entire patient population (p = 0.03). Among the proteins analyzed, bcl-2 expression before treatment and p27kip1 expression analyzed after 48 hours of corticotherapy were the sole variables associated with significant differences in disease free survival duration in the entire patient population (p < 0.01 and p = 0.04 respectively) or in the B-cell ALL subgroup (p < 0.01). Comparable results were obtained for the overall survival data. The significance of these results is discussed but such a study on blood blast cells needs to be validated in a larger series.

[Cyclin dependent kinase inhibitors and replicative senescence]. / Inhibiteurs des kinases dépendantes des cyclines et sénescence réplicative.

Replicative senescence is defined for human diploid fibroblasts in culture as a cell growth arrest appearing beyond 50 +/- 10 population doublings and associated with telomeres' shortening. This phenomenon shows an increased expression of growth cell inhibitors: p21Waf1 described as an universal CDK inhibitor and p16INK4a as a specific inhibitor for both G1 phase kinases CDK4 and CDK6. The cell proliferation inhibitor p14ARF, product of INK4a/ARF locus is involved in replicative senescence too. Overexpression or homozygotic deletion of these inhibitors demonstrated their role in senescence induction. These proteins are involved in two different metabolic pathways, the first including p53, represented by E2F, ARF, MDM2, p53, p21Waf1, and the second concerning pRb and p16INK4a. These two pathways present numerous interactions and the polymerase (PARP) in relation with p53 and activated by telomere shortening might represent via p21Waf1 a link between this shortening and cell cycle control. An another metabolic pathway involving PTEN and p27KIP1 is discussed in senescent-like phenotype induction, but its activity in replicative senescent is uncertain.