title: Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression.
abstract: Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are clonal myeloid disorders with increased production of terminally differentiated cells. The disease course is generally chronic, but some patients show disease progression (secondary myelofibrosis or accelerated phase) and/or leukemic transformation. We investigated chromosomal aberrations in 408 MPN samples using high-resolution single-nucleotide polymorphism microarrays to identify disease-associated somatic lesions. Of 408 samples, 37.5% had a wild-type karyotype and 62.5% harbored at least 1 chromosomal aberration. We identified 25 recurrent aberrations that were found in 3 or more samples. An increased number of chromosomal lesions was significantly associated with patient age, as well as with disease progression and leukemic transformation, but no association was observed with MPN subtypes, Janus kinase 2 (JAK2) mutational status, or disease duration. Aberrations of chromosomes 1q and 9p were positively associated with disease progression to secondary myelofibrosis or accelerated phase. Changes of chromosomes 1q, 7q, 5q, 6p, 7p, 19q, 22q, and 3q were positively associated with post-MPN acute myeloid leukemia. We mapped commonly affected regions to single target genes on chromosomes 3p (forkhead box P1 [FOXP1]), 4q (tet oncogene family member 2 [TET2]), 7p (IKAROS family zinc finger 1 [IKZF1]), 7q (cut-like homeobox 1 [CUX1]), 12p (ets variant 6 [ETV6]), and 21q (runt-related transcription factor 1 [RUNX1]). Our data provide insight into the genetic complexity of MPNs and implicate new genes involved in disease progression.
authors.affiliation: Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Klampfl
authors.forename: Ashot
authors.initials: A
authors.lastname: Harutyunyan
authors.forename: Tiina
authors.initials: T
authors.lastname: Berg
authors.forename: Bettina
authors.initials: B
authors.lastname: Gisslinger
authors.forename: Martin
authors.initials: M
authors.lastname: Schalling
authors.forename: Klaudia
authors.initials: K
authors.lastname: Bagienski
authors.forename: Damla
authors.initials: D
authors.lastname: Olcaydu
authors.forename: Francesco
authors.initials: F
authors.lastname: Passamonti
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.forename: Roland
authors.initials: R
authors.lastname: Jäger
authors.forename: Lisa
authors.initials: L
authors.lastname: Pieri
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: Heinz
authors.initials: H
authors.lastname: Gisslinger
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
mesh_terms: D002908:Chronic Disease; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D007621:Karyotyping; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2