High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib.
Imatinib, a specific inhibitor of the Abl, Kit and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, is effective in all phases of chronic myelogenous leukemia. While responses in chronic phase are usually durable, resistance frequently develops in patients with advanced disease after an initial response. Several mechanisms of resistance have been demonstrated in vivo, including mutations in the BCR-ABL kinase domain and amplification of the BCR-ABL gene. We analyzed cytogenetics and screened for mutations of the BCR-ABL kinase domain as well as the activation loops of KIT and PDGFRA and B in 49 patients with CML or Ph-positive acute lymphoblastic leukemia with resistance to imatinib. Mutations in the kinase domain of BCR-ABL were detected in 51.6% of patients with secondary resistance but not in patients with primary resistance. Three of these mutations have not been described before (T315D, F359D and D276G). By contrast, KIT and PDGFRA and B were consistently wildtype. Clonal evolution prior to imatinib was present in 68.8% of patients with primary resistance and in 45.5% with secondary resistance. Additional cytogenetic aberrations developed in 18.2% of patients at the time of relapse. Our results confirm the high frequency of BCR-ABL kinase domain mutations in patients with secondary resistance to imatinib and exclude mutations of the activation loops of KIT, PDGFRA and PDGFRB as possible causes of resistance in patients without ABL mutations.
Al-Ali
Haifa-Kathrin
HK
Department of Hematology, University of Leipzig, Germany.
Heinrich
Michael Charles
MC
Lange
Thoralf
T
Krahl
Rainer
R
Mueller
Matthias
M
Müller
Christel
C
Niederwieser
Dietger
D
Druker
Brian James
BJ
Deininger
Michael Werner Nikolaus
MW
D001549:Benzamides; D002999:Clone Cells; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D005787:Gene Frequency; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics; D012008:Recurrence
D001549:Benzamides; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D016044:Fusion Proteins, bcr-abl