title: Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status.
abstract: To study clonal evolution in chronic myeloid leukemia (CML), we searched for BCR-ABL-independent gene mutations in both Philadelphia chromosome (Ph)-negative and Ph-positive clones in 29 chronic-phase CML patients by targeted deep sequencing of 25 genes frequently mutated in myeloid disorders. Ph-negative clones were analyzed in 14 patients who developed clonal cytogenetic abnormalities in Ph-negative cells during treatment with tyrosine kinase inhibitors (TKI). Mutations were detected in 6/14 patients (43%) affecting the genes DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1 and ZRSR2. In two patients, the mutations were also found in corresponding Ph-positive diagnostic samples. To further investigate Ph-positive clones, 15 randomly selected CML patients at diagnosis were analyzed. Somatic mutations additional to BCR-ABL were found in 5/15 patients (33%) affecting ASXL1, DNMT3A, RUNX1 and TET2. Analysis of individual hematopoietic colonies at diagnosis revealed that most mutations were part of the Ph-positive clone. In contrast, deep sequencing of subsequent samples during TKI treatment revealed one DNMT3A mutation in Ph-negative cells that was also present in Ph-positive cells at diagnosis, implying that the mutation preceded the BCR-ABL rearrangement. In summary, BCR-ABL-independent gene mutations were frequently found in Ph-negative and Ph-positive clones of CML patients and may be considered as important cofactors in the clonal evolution of CML.
authors.affiliation: Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Rinke
authors.affiliation: Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Schäfer
authors.affiliation: MLL Münchner Leukämie Labor, München, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schnittger
authors.affiliation: MLL Münchner Leukämie Labor, München, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kohlmann
authors.affiliation: Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Obstfelder
authors.affiliation: Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kunert
authors.affiliation: Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Ziermann
authors.affiliation: Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Winkelmann
authors.affiliation: Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Eigendorff
authors.affiliation: MLL Münchner Leukämie Labor, München, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: MLL Münchner Leukämie Labor, München, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Haferlach
authors.affiliation: Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hochhaus
authors.affiliation: Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Ernst
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002869:Chromosome Aberrations; D060965:Clonal Evolution / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010677:Philadelphia Chromosome; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl