title: Decreased sensitivity of 17p-deleted chronic lymphocytic leukemia cells to a small molecule BCL-2 antagonist ABT-737.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  The current data indicated that p53 dysfunction may lead to decreased apoptosis induction by ABT-737.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
authors.forename: Seshagiri
authors.initials: S
authors.lastname: Duvvuri
authors.forename: Vivian
authors.initials: V
authors.lastname: Ruvolo
authors.forename: Felipe
authors.initials: F
authors.lastname: Samaniego
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009596:Nitrophenols / Q000494:pharmacology* / Q000627:therapeutic use; D010597:Pharmacogenetics; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D058496:Smith-Magenis Syndrome; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000235:genetics
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D007093:Imidazoles; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C482205:nutlin 3