title: Enhanced ABL-inhibitor-induced MAPK-activation in T315I-BCR-ABL-expressing cells: a potential mechanism of altered leukemogenicity.
abstract: BACKGROUND
  Targeted treatment of chronic myelogenous leukemia using imatinib has dramatically improved patient outcome. However, residual disease can be detected in the majority of patients treated with imatinib. Compensatory activation of MAP kinases (MAPK1/2) in response to BCR-ABL-inhibitors has been reported as a potential cytokine-dependent resistance mechanism leading to the rescue of leukemic progenitor cells.
  
  
  METHODS
  Differential MAPK-modulating activity of clinically approved tyrosine kinase inhibitors was assessed in vitro using BCR-ABL-transformed cells. CD34+-enriched progenitors of newly diagnosed chronic myelogenous leukemia patients were exposed to tyrosine kinase inhibitors. MAPK-signaling was studied by Western blot technique. Proliferation assays were used to analyze response to antileukemic treatment.
  
  
  RESULTS
  The ABL-inhibitors imatinib and nilotinib activate MAPKs in CD34+ chronic myelogenous leukemia progenitor cells, whereas treatment with the SRC/ABL-inhibitor dasatinib does not affect MAPK-activation at clinically relevant concentrations. Similar results are seen in BCR-ABL-transformed cells in the presence of interleukin-3 (IL-3). Experiments using BCR-ABL-mutant T315I, a resistance mutation not amenable to tyrosine kinase inhibitor binding, demonstrate that ABL-inhibitor-induced MAPK-activation does not depend on BCR-ABL-inhibition and cannot be prevented by selective SRC-inhibition. However, BCR-ABL-T315I enhances MAPK-activation, suggesting a T315I-dependent positive feedback of MAPK-activation. An autocrine IL-3-loop as trigger for aberrant T315I-dependent MAPK-activation was excluded.
  
  
  CONCLUSIONS
  Aberrant MAPK-activation triggered by ABL-inhibitors and positively regulated by BCR-ABL kinase mutation T315I might be an experimental explanation for the clinical observation that patients carrying high-resistance mutations show a highly aggressive course of their disease when tyrosine kinase inhibitor treatment is not discontinued in time.
authors.affiliation: III. Medizinische Universitätsklinik, Universitätsmedizin Mannheim der Universität Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Härtel
authors.forename: Thomas
authors.initials: T
authors.lastname: Klag
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hanfstein
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mueller
authors.forename: Thomas
authors.initials: T
authors.lastname: Schenk
authors.forename: Philipp
authors.initials: P
authors.lastname: Erben
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Paul
authors.initials: P
authors.lastname: La Rosée
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007377:Interleukin-3 / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D007377:Interleukin-3; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C498826:nilotinib; D000069439:Dasatinib
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