nutlin-3a and Smith-Magenis-Syndrome

Despite the high complete response rates achieved with fludarabine-based regimens, relapse is inevitable in chronic lymphocytic leukemia (CLL). Relapsed patients often acquire deletions of the short arm of chromosome 17 (del[17p]), which are closely associated with tumor protein 53 (TP53) mutations. Wild-type p53 up-regulates and activates B-cell CLL/lymphoma 2 (BCL-2)-associated X protein (BAX), and it down-regulates and inactivates BCL-2. The small-molecule BCL-2 inhibitor ABT-737 induces apoptosis in a BAX-dependent and BCL-2 homologous antagonist-killer (BAK)-dependent manner. The role of p53 in sensitivity of CLL cells to BCL-2 inhibition has not been extensively investigated.. The authors investigated the association of del(17p) with ABT-737 sensitivity in CLL cells from 50 patients. Stable p53 and BAX knockdown cells were used for mechanistic studies.. CLL cells with del(17p) were less sensitive to ABT-737-induced BAX activation and apoptosis than CLL cells without del(17p) (39% ± 7.3% vs 63.7% ± 2.9% [specific annexin V induction]; P < .01). A positive correlation between the degrees of apoptosis induced by ABT-737 and by the p53-activating binding protein homolog murine double minute (MDM2) antagonist nutlin-3a (correlation coefficient [r] = 0.75; P < .0001) was observed. CLL cells with del(17p) expressed lower levels of BAX than those without del(17p) (0.67 ± 0.12 vs 1.27 ± 0.10 in relative protein expression levels; P < .01). Knockdown of p53 or BAX in leukemia cells resulted in decreased apoptosis induced by ABT-737.. The current data indicated that p53 dysfunction may lead to decreased apoptosis induction by ABT-737.

Topics: Aged; Aged, 80 and over; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Cells, Cultured; Chromosome Deletion; Chromosomes, Human, Pair 17; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Nitrophenols; Pharmacogenetics; Piperazines; Proto-Oncogene Proteins c-bcl-2; Smith-Magenis Syndrome; Sulfonamides; Treatment Outcome; Tumor Suppressor Protein p53