title: Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations.
abstract: In AML, cooperation of mutations suppressing differentiation ('class-II-mutations') with 'class-I-mutations' increasing cell proliferation is frequent. In rare cases of myeloid malignancies, the BCR-ABL1 fusion was reported to cooperate as class-I-mutation with class-II-mutations, but most cases had to be classified as blast phase of chronic myeloid leukaemia (CML). We identified five cases of Philadelphia positive subclones in AML occurring in coincidence with other genetic lesions: 1:220 patients with inv(16)/CBFB-MYH11 (0·5%), 2:272 AML cases with t(8;21)/RUNX1-RUNX1T1 (0·7%), 1:1029 NPM1-mutated AML (0·1%), and one patient with s-AML following MDS with a 5q-deletion. Four patients had m-BCR (e1a2) BCR-ABL1 transcripts; one case only had an M-BCR (b3a2) breakpoint. These cases allow some interesting conclusions: The BCR-ABL1 rearrangement apparently can cooperate with the NPM1 mutation similar to other class-I-mutations. The identification of Philadelphia positive subclones in <1% of patients with CBF-leukaemias fits well with previous observations that most CBF-AML are accompanied by activating mutations in genes enhancing proliferation. Since we observed the occurrence of the Philadelphia positive subclones at diagnosis, at relapse, or throughout the disease, the time point of the emergence of Philadelphia subclones seems variable in AML. Clinical research should further concentrate on Philadelphia positive subclones in AML to assess the clinical impact.
authors.affiliation: Clinic for Stem Cell Transplantation, University Cancer Center Hamburg, Hamburg.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bacher
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Tamara
authors.initials: T
authors.lastname: Alpermann
authors.forename: Melanie
authors.initials: M
authors.lastname: Zenger
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Dietrich W
authors.initials: DW
authors.lastname: Beelen
authors.forename: Michael
authors.initials: M
authors.lastname: Uppenkamp
authors.forename: Mathias
authors.initials: M
authors.lastname: Rummel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kern
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
mesh_terms: D000328:Adult; D000368:Aged; D002871:Chromosome Banding / Q000379:methods; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D050660:Core Binding Factors / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015321:Gene Rearrangement; D006801:Humans; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000090243:Nucleophosmin; D012189:Retrospective Studies; D014178:Translocation, Genetic
chemical_list: D050660:Core Binding Factors; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D016044:Fusion Proteins, bcr-abl