title: Quantitative monitoring of BCR/ABL1 mutants for surveillance of subclone-evolution, -expansion, and -depletion in chronic myeloid leukaemia.
abstract: BACKGROUND
  In chronic myeloid leukaemia (CML), clonal evolution with resistance to tyrosine kinase inhibitors (TKIs) is often triggered by BCR/ABL1 mutations. However, in the context of the complex pro-oncogenic signalling networks which ultimately lead to clonal expansion and disease progression, the exact contribution of BCR/ABL1 mutants remains uncertain. Recent data indicate that detection of BCR/ABL1 mutant subclones does not permit prediction of their expansion dynamics and their potential to become drivers of resistant disease.
  
  
  METHODS
  To determine the patterns of clonal evolution and the distinct proliferation kinetics of individual BCR/ABL1 mutants during treatment, we employed ligase-dependent polymerase chain reaction (LD-PCR) analysis for quantitative surveillance of CML subclones with various tyrosine kinase domain (TKD) mutations including M244V, L248V, G250E, E255K, T315I, F317L-A/G, M351T and F359V.
  
  
  RESULTS
  Inadequate treatment responses were observed in 27 of 100 patients investigated and 16 were found to bear one or more BCR/ABL1 TKD mutations in separate subclones. Rapid subclone expansion upon onset or switch of TKI treatment was common and sometimes preceded corresponding changes in BCR/ABL1 transcript levels. Mutant subclones were found to respond differentially and sometimes unexpectedly to various treatment modalities. Decline and persistent depletion of specific mutation-bearing subclones in response to treatment could be documented by LD-PCR surveillance.
  
  
  CONCLUSIONS
  The observations show that quantitative monitoring of mutant BCR/ABL1 subclones by LD-PCR is a powerful tool for detection of clonal evolution, subclone-expansion and subclone-depletion and can contribute to optimised management of patients with CML.
authors.affiliation: Children's Cancer Research Institute, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Preuner
authors.forename: G
authors.initials: G
authors.lastname: Mitterbauer
authors.forename: C
authors.initials: C
authors.lastname: Mannhalter
authors.forename: S
authors.initials: S
authors.lastname: Herndlhofer
authors.forename: W R
authors.initials: WR
authors.lastname: Sperr
authors.forename: P
authors.initials: P
authors.lastname: Valent
authors.forename: T
authors.initials: T
authors.lastname: Lion
mesh_terms: D060965:Clonal Evolution / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D017354:Point Mutation; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016044:Fusion Proteins, bcr-abl