Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms.
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.
Thoennissen
Nils H
NH
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
Krug
Utz O
UO
Lee
Dhong Hyun Tony
DH
Kawamata
Norihiko
N
Iwanski
Gabriela B
GB
Lasho
Terra
T
Weiss
Tamara
T
Nowak
Daniel
D
Koren-Michowitz
Maya
M
Kato
Motohiro
M
Sanada
Masashi
M
Shih
Lee-Yung
LY
Nagler
Arnon
A
Raynaud
Sophie D
SD
Müller-Tidow
Carsten
C
Mesa
Ruben
R
Haferlach
Torsten
T
Gilliland
D Gary
DG
Tefferi
Ayalew
A
Ogawa
Seishi
S
Koeffler
H Phillip
HP
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
D009363:Neoplasm Proteins; C507924:JAK2 protein, human; D053614:Janus Kinase 2