Role of BCL-2 and cell cycle regulatory proteins for corticosensitivity assessment in childhood acute lymphoblastic leukaemia.
Results of treatment in childhood acute lymphoblastic leukaemia (ALL) remain unsatisfactory because relapses occur even after high-dose chemotherapy. Corticosensitivity is used in numerous therapeutic trials as a prognostic factor for treatment choice. The aim of this study was to evaluate the role of cell cycle regulatory protein expression before and during the first 48 h of corticotherapy for predicting corticosensitivity. Fifty-two children presenting with ALL were studied at diagnosis and during the first 48 h of treatment for cell proliferation and apoptosis level by measurement of DNA content, and for expression of several cell proliferation regulatory proteins by means of Western blot. Glucocorticoids induced a significant decrease in the percentage of cells in S-phase and in CDK1, CDK4 and CDK6 expression and an increase in the percentage of cells in subG1 peak. Two criteria for corticosensitivity were used: (i) the number of blast cells after 7 d of treatment with a threshold at 1 x 109/l (usual criterion), (ii) the J8/J1 blast cell ratio, which is independent from initial leucocytosis. Bcl-2 expression at diagnosis was the best predictive variable for the usual corticosensitivity criterion in B- and T-cell ALL. For the second criterion, in B-cell ALL, p21waf1 expression at diagnosis was the sole (albeit poorly) predictive variable, whereas bcl-2 remained of high interest in T-cell ALL. Interestingly, these proteins, bcl-2 and p21waf1, are associated with prolonged cell lifespan and their increased expression is often linked to poor response to cytotoxic drugs. Such preliminary results call for subsequent studies on large independent sets of T-cell and B-cell lineage ALL in order to confirm the J8/J1 blast cell ratio value as well as the role of bcl-2 and p21waf1 expression in predicting corticosensitivity.
Baghdassarian
N
N
Laboratoire de Cytologie Analytique, Université Claude Bernard, MESRT JE 1879, Lyon, France.
Bertrand
Y
Y
Ffrench
P
P
Duhaut
P
P
Bryon
P A
PA
Ffrench
M
M
D000293:Adolescent; D015415:Biomarkers / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D002899:Chromosomes, Human, Pair 9; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement; D005938:Glucocorticoids / Q000378:metabolism / Q000627:therapeutic use*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D008297:Male; D051788:Myeloid-Lymphoid Leukemia Protein; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011237:Predictive Value of Tests; D011239:Prednisolone / Q000378:metabolism / Q000627:therapeutic use*; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D011519:Proto-Oncogenes; D012372:ROC Curve; D014157:Transcription Factors; D014178:Translocation, Genetic; D017211:Treatment Failure
D015415:Biomarkers; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; C497422:KMT2A protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011239:Prednisolone; D011495:Histone-Lysine N-Methyltransferase