title: c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches.
abstract: In lymph node (LN) proliferation centers in chronic lymphocytic leukemia (CLL), the environment protects from apoptotic and cytotoxic triggers. Here, we aimed to define the molecular basis for the increased drug resistance and searched for novel strategies to circumvent it. The situation in CLL LN could be mimicked by prolonged in vitro CD40 stimulation, which resulted in up-regulation of antiapoptotic Bcl-xL, A1/Bfl-1, and Mcl-1 proteins, and afforded resistance to various classes of drugs (fludarabine, bortezomib, roscovitine). CD40 stimulation also caused ERK-dependent reduction of Bim-EL protein, but ERK inhibition did not prevent drug resistance. Drugs combined with sublethal doses of the BH3-mimetic ABT-737 displayed partial and variable effects per individual CD40-stimulated CLL. The antiapoptotic profile of CD40-triggered CLL resembled BCR-Abl-dependent changes seen in chronic myeloid leukemia (CML), which prompted application of c-Abl inhibitors imatinib or dasatinib. Both compounds, but especially dasatinib, prevented the entire antiapoptotic CD40 program in CLL cells, and restored drug sensitivity. These effects also occurred in CLL samples with dysfunctional p53. Importantly, ex vivo CLL LN samples also displayed strong ERK activation together with high Bcl-xL and Mcl-1 but low Bim levels. These data indicate that CLL cells in chemoresistant niches may be sensitive to therapeutic strategies that include c-Abl inhibitors.
authors.affiliation: Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Delfine Y H
authors.initials: DY
authors.lastname: Hallaert
authors.forename: Annelieke
authors.initials: A
authors.lastname: Jaspers
authors.forename: Carel J
authors.initials: CJ
authors.lastname: van Noesel
authors.forename: Marinus H J
authors.initials: MH
authors.lastname: van Oers
authors.forename: Arnon P
authors.initials: AP
authors.lastname: Kater
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D019013:CD40 Antigens / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008198:Lymph Nodes; D008565:Membrane Proteins / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D055153:Stem Cell Niche / Q000473:pathology*; D015854:Up-Regulation; D051020:bcl-X Protein / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D019013:CD40 Antigens; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D016315:Proto-Oncogene Proteins c-abl; D048049:Extracellular Signal-Regulated MAP Kinases