title: Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia.
abstract: Imatinib mesylate (IM) binds to the BCR-ABL protein, inhibiting its kinase activity and effectively controlling diseases driven by this kinase. IM resistance has been associated with kinase mutations or increased BCR-ABL expression. However, disease progression may be mediated by other mechanisms that render tumor cells independent of BCR-ABL. To demonstrate this potential, IM-resistant cells were found in chronic myelogenous leukemia patients with continuous BCR-ABL gene expression but undetectable BCR-ABL protein expression. These cells were unresponsive to IM and acquired BCR-ABL-independent signaling characteristics. IM resistance in some patients may be mediated through loss of kinase target dependence.
authors.affiliation: Department of Bioimmunotherapy, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ndonato@mdanderson.org
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Donato
authors.forename: Ji Y
authors.initials: JY
authors.lastname: Wu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stapley
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.forename: Ralph
authors.initials: R
authors.lastname: Arlinghaus
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
authors.forename: Shishir
authors.initials: S
authors.lastname: Shishodia
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
authors.forename: Kimberly
authors.initials: K
authors.lastname: Hayes
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.forename: Shishir
authors.initials: S
authors.lastname: Shishodin
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D017403:In Situ Hybridization; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D020079:Terminal Repeat Sequences / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl