title: Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms.
abstract: Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and primary myelofibrosis show an inherent tendency for transformation into leukemia (MPN-blast phase), which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, examined chromosomal abnormalities by high-resolution single nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. Frequent genomic alterations were found in MPN after leukemic transformation with up to 3-fold more genomic changes per sample compared with samples in chronic phase (P < .001). We identified commonly altered regions involved in disease progression including not only established targets (ETV6, TP53, and RUNX1) but also new candidate genes on 7q, 16q, 19p, and 21q. Moreover, trisomy 8 or amplification of 8q24 (MYC) was almost exclusively detected in JAK2V617F(-) cases with MPN-blast phase. Remarkably, copy number-neutral loss of heterozygosity (CNN-LOH) on either 7q or 9p including homozygous JAK2V617F was related to decreased survival after leukemic transformation (P = .01 and P = .016, respectively). Our high-density SNP-array analysis of MPN genomes in the chronic compared with leukemic stage identified novel target genes and provided prognostic insights associated with the evolution to leukemia.
authors.affiliation: Division of Hematology and Oncology, Cedars-Sinai Medical Center, University of California Los Angeles School of Medicine, Los Angeles, CA 90048, USA. nils.thoennissen@cshs.org
authors.forename: Nils H
authors.initials: NH
authors.lastname: Thoennissen
authors.forename: Utz O
authors.initials: UO
authors.lastname: Krug
authors.forename: Dhong Hyun Tony
authors.initials: DH
authors.lastname: Lee
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kawamata
authors.forename: Gabriela B
authors.initials: GB
authors.lastname: Iwanski
authors.forename: Terra
authors.initials: T
authors.lastname: Lasho
authors.forename: Tamara
authors.initials: T
authors.lastname: Weiss
authors.forename: Daniel
authors.initials: D
authors.lastname: Nowak
authors.forename: Maya
authors.initials: M
authors.lastname: Koren-Michowitz
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Sophie D
authors.initials: SD
authors.lastname: Raynaud
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Ruben
authors.initials: R
authors.lastname: Mesa
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000368:Aged; D001752:Blast Crisis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002877:Chromosomes, Human / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010677:Philadelphia Chromosome; D015995:Prevalence; D015996:Survival Rate
chemical_list: D009363:Neoplasm Proteins; C507924:JAK2 protein, human; D053614:Janus Kinase 2