title: Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors.
abstract: BACKGROUND
  BCR-ABL kinase domain (KD) mutations are detected in approximately 45% of patients with imatinib-resistant chronic myeloid leukemia. Patterns of KD mutations in Philadelphia chromosome (Ph)-positive acute lympho- blastic leukemia (ALL) are less well studied.
  
  
  METHODS
  The authors assessed KD mutations in patients with recurrent Ph-positive ALL after treatments that included 1 or more kinase inhibitors (n = 24 patients) or no prior kinase inhibitor (KI) therapy (n = 12 patients).
  
  
  RESULTS
  ABL KD mutations were detected by direct sequencing in 15 of 17 patients (88%) who had recurrent Ph-positive ALL and received prior imatinib (n = 16) or dasatinib (n = 1) treatment and in 6 of 7 patients (86%) who had resistant/recurrent tumors treated with >or=2 KIs compared with 0 of 12 patients with recurrent Ph-positive ALL who never received KIs. A restricted set of mutations was observed, mostly Y253H and T315I, and were detected on average 10 months after KI initiation, and mutations were not detected in the initial tumor samples before KI therapy in 12 patients who were assessed. Using a more sensitive pyrosequencing method, mutations were not detected at codons 315 and 253 in the diagnostic samples from those 12 patients or in 30 patients with Ph-positive ALL who never developed recurrent disease.
  
  
  CONCLUSIONS
  ABL KD mutations, especially at codons 315 and 253, emerged at the time of disease recurrence in the vast majority of patients who had Ph-positive ALL and received maintenance KI therapy. Thus, the authors concluded that ongoing KI exposure may alter the patterns of recurrence and favor the outgrowth of clones with KI-resistant mutations.
authors.affiliation: Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. dajones@mdanderson.org
authors.forename: Dan
authors.initials: D
authors.lastname: Jones
authors.forename: Deborah
authors.initials: D
authors.lastname: Thomas
authors.forename: C Cameron
authors.initials: CC
authors.lastname: Yin
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.forename: Megan
authors.initials: M
authors.lastname: Breeden
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhao
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D010879:Piperazines / Q000627:therapeutic use; D017354:Point Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use; D012008:Recurrence; D016879:Salvage Therapy
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl