title: Rapid clonal shifts in response to kinase inhibitor therapy in chronic myelogenous leukemia are identified by quantitation mutation assays.
abstract: Treatment of CML with the tyrosine kinase inhibitor (TKI) imatinib mesylate results in the emergence of point mutations within the kinase domain (KD) of the BCR-ABL1 fusion transcript. The introduction of next-generation TKIs that can overcome the effects of some BCR-ABL1 KD mutations requires quantitative mutation profiling methods to assess responses. We report the design and validation of such quantitative assays, using pyrosequencing and mutation-specific RT-PCR techniques, to allow sequential monitoring and illustrate their use in tracking specific KD mutations (e.g. G250E, T315I, and M351T) following changes in therapy. Pyrosequencing and mutation-specific RT-PCR allows sequential monitoring of specific mutations and identification of rapid clonal shifts in response to kinase inhibitor therapy in CML. Rapid reselection of TKI-resistant clones occurs following therapy switch in CML.
authors.affiliation: Department of Hematopathology, the University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. cyin@mdanderson.org
authors.forename: C Cameron
authors.initials: CC
authors.lastname: Yin
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: John
authors.initials: J
authors.lastname: Galbincea
authors.forename: Neelima
authors.initials: N
authors.lastname: Reddy
authors.forename: Megan
authors.initials: M
authors.lastname: Breeden
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.forename: Dan
authors.initials: D
authors.lastname: Jones
mesh_terms: D019943:Amino Acid Substitution; D001549:Benzamides; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl