title: Tipping the Noxa/Mcl-1 balance overcomes ABT-737 resistance in chronic lymphocytic leukemia.
abstract: OBJECTIVE
  Chronic lymphocytic leukemia (CLL) cells in lymph nodes (LN), from which relapses are postulated to originate, display an antiapoptotic profile in contrast to CLL cells from peripheral blood (PB). The BH3 mimetic ABT-737 antagonizes the antiapoptotic proteins Bcl-X(L) and Bcl-2 but not Mcl-1 or Bfl-1. Previously, it was shown that CD40-stimulated CLL cells were resistant to ABT-737. We aimed to define which antiapoptotic proteins determine resistance to ABT-737 in CLL and whether combination of known antileukemia drugs and ABT-737 was able to induce apoptosis of CD40-stimulated CLL cells.
  
  
  METHODS
  To mimic the LN microenvironment, PB lymphocytes of CLL patients were cultured on feeder cells expressing CD40L and treated with ABT-737 with or without various drugs. In addition, we carried out overexpression or knockdown of pro- and antiapoptotic proteins in immortalized primary B cells.
  
  
  RESULTS
  Upon CD40 stimulation patient-specific variations in ABT-737 sensitivity correlated with differences in levels of Mcl-1 and its antagonist Noxa. Knockdown of Noxa, as well as Mcl-1 overexpression, corroborated the importance of the Noxa/Mcl-1 ratio in determining the response to ABT-737. Inhibition of NF-κB resulted in increased Noxa levels and enhanced sensitivity to ABT-737. Interestingly, increasing the Noxa/Mcl-1 ratio, by decreasing Mcl-1 (dasatinib and roscovitine) or increasing Noxa levels (fludarabine and bortezomib), resulted in synergy with ABT-737.
  
  
  CONCLUSIONS
  Thus, the Noxa/Mcl-1 balance determines sensitivity to ABT-737 in CD40-stimulated CLL cells. These data provide a rationale to investigate the combination of drugs which enhance the Noxa/Mcl-1 balance with ABT-737 to eradicate CLL in chemoresistant niches.
authors: Departments of Hematology and Experimental Immunology, and Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. j.m.tromp@amc.uva.nl
authors: Jacqueline M
authors: JM
authors: Tromp
authors: Christian R
authors: CR
authors: Geest
authors: Esther C W
authors: EC
authors: Breij
authors: Judith A
authors: JA
authors: Elias
authors: Jacoline
authors: J
authors: van Laar
authors: Dieuwertje M
authors: DM
authors: Luijks
authors: Arnon P
authors: AP
authors: Kater
authors: Tim
authors: T
authors: Beaumont
authors: Marinus H J
authors: MH
authors: van Oers
authors: Eric
authors: E
authors: Eldering
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D019013:CD40 Antigens / Q000378:metabolism / Q000502:physiology; D023201:CD40 Ligand / Q000378:metabolism / Q000502:physiology; D018920:Coculture Techniques; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; D001713:Biphenyl Compounds; D019013:CD40 Antigens; C579094:Mcl1 protein, mouse; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009596:Nitrophenols; C498702:PMAIP1 protein, human; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D013449:Sulfonamides; D013844:Thiazoles; D023201:CD40 Ligand; D048051:p38 Mitogen-Activated Protein Kinases; D014740:Vidarabine; C024352:fludarabine; D000069439:Dasatinib