title: BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships.
abstract: BCR-ABL1 compound mutations can confer high-level resistance to imatinib and other ABL1 tyrosine kinase inhibitors (TKIs). The third-generation ABL1 TKI ponatinib is effective against BCR-ABL1 point mutants individually, but remains vulnerable to certain BCR-ABL1 compound mutants. To determine the frequency of compound mutations among chronic myeloid leukemia patients on ABL1 TKI therapy, in the present study, we examined a collection of patient samples (N = 47) with clear evidence of 2 BCR-ABL1 kinase domain mutations by direct sequencing. Using a cloning and sequencing method, we found that 70% (33/47) of double mutations detected by direct sequencing were compound mutations. Sequential, branching, and parallel routes to compound mutations were common. In addition, our approach revealed individual and compound mutations not detectable by direct sequencing. The frequency of clones harboring compound mutations with more than 2 missense mutations was low (10%), whereas the likelihood of silent mutations increased disproportionately with the total number of mutations per clone, suggesting a limited tolerance for BCR-ABL1 kinase domain missense mutations. We conclude that compound mutations are common in patients with sequencing evidence for 2 BCR-ABL1 mutations and frequently reflect a highly complex clonal network, the evolution of which may be limited by the negative impact of missense mutations on kinase function.
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Jamshid S
authors.initials: JS
authors.lastname: Khorashad
authors.forename: Todd W
authors.initials: TW
authors.lastname: Kelley
authors.forename: Philippe
authors.initials: P
authors.lastname: Szankasi
authors.forename: Clinton C
authors.initials: CC
authors.lastname: Mason
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.forename: Lauren T
authors.initials: LT
authors.lastname: Adrian
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Zabriskie
authors.forename: Thoralf
authors.initials: T
authors.lastname: Lange
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Estrada
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Pomicter
authors.forename: Anna M
authors.initials: AM
authors.lastname: Eiring
authors.forename: Ira L
authors.initials: IL
authors.lastname: Kraft
authors.forename: David J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Gu
authors.forename: Mary
authors.initials: M
authors.lastname: Alikian
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Reid
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
authors.forename: David
authors.initials: D
authors.lastname: Marin
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
mesh_terms: D001549:Benzamides; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl