title: Philadelphia-positive acute lymphoblastic leukemia patients already harbor BCR-ABL kinase domain mutations at low levels at the time of diagnosis.
abstract: BACKGROUND
  In patients with Philadelphia-positive acute lymphoblastic leukemia, resistance to treatment with tyrosine kinase inhibitors is frequent and most often associated with the development of point mutations in the BCR-ABL kinase domain. We aimed to assess: (i) in how many patients BCR-ABL kinase domain mutations are already detectable at relatively low levels at the time of diagnosis, and (ii) whether mutation detection correlates with subsequent response to therapy.
  
  
  METHODS
  We retrospectively analyzed samples collected at diagnosis from 15 patients with Philadelphia-positive acute lymphoblastic leukemia who subsequently received tyrosine kinase inhibitor therapy (dasatinib) by cloning the BCR-ABL kinase domain in a bacterial vector and sequencing 200 independent clones per sample.
  
  
  RESULTS
  Mutations at relatively low levels (2-4 clones out of 200) could be detected in all patients--eight who relapsed and seven who achieved persistent remission. Each patient had evidence of two to eight different mutations, the majority of which have never been reported in association with resistance to tyrosine kinase inhibitors. In two patients out of six who relapsed because of a mutation, the mutation (a T315I) was already detectable in a few clones at the time of diagnosis. On the other hand, a patient who was found to harbor an F317L mutation is in persistent remission on dasatinib.
  
  
  CONCLUSIONS
  Our results suggest that the BCR-ABL kinase domain is prone to randomly accumulate point mutations in Philadelphia-positive acute lymphoblastic leukemia, although the presence of these mutations in a relatively small leukemic subclone does not always preclude a primary response to tyrosine kinase inhibitors.
authors.affiliation: Department of Hematology and Oncological Sciences L e A Seràgnoli, University of Bologna, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.forename: Antonella
authors.initials: A
authors.lastname: Vitale
authors.forename: Angela
authors.initials: A
authors.lastname: Poerio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gnani
authors.forename: Sabrina
authors.initials: S
authors.lastname: Colarossi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cimino
authors.forename: Loredana
authors.initials: L
authors.lastname: Elia
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lonetti
authors.forename: Marco
authors.initials: M
authors.lastname: Vignetti
authors.forename: Stefania
authors.initials: S
authors.lastname: Paolini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Meloni
authors.forename: Valeria
authors.initials: V
authors.lastname: di Maio
authors.forename: Cristina
authors.initials: C
authors.lastname: Papayannidis
authors.forename: Marilina
authors.initials: M
authors.lastname: Amabile
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D023061:Gene Order; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D016044:Fusion Proteins, bcr-abl