TY - JOUR
T1 - Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms
AU - Thoennissen, Nils H.
AU - Krug, Utz O.
AU - Lee, Dhong Hyun Tony
AU - Kawamata, Norihiko
AU - Iwanski, Gabriela B.
AU - Lasho, Terra
AU - Weiss, Tamara
AU - Nowak, Daniel
AU - Koren-Michowitz, Maya
AU - Kato, Motohiro
AU - Sanada, Masashi
AU - Shih, Lee Yung
AU - Nagler, Arnon
AU - Raynaud, Sophie D.
AU - Müller-Tidow, Carsten
AU - Mesa, Ruben
AU - Haferlach, Torsten
AU - Gilliland, D. Gary
AU - Tefferi, Ayalew
AU - Ogawa, Seishi
AU - Phillip Koeffler, H.
PY - 2010/4/8
Y1 - 2010/4/8
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2009-07-235119
DO - 10.1182/blood-2009-07-235119
M3 - Article
C2 - 20068225
AN - SCOPUS:77950994977
SN - 0006-4971
VL - 115
SP - 2882
EP - 2890
JO - Blood
JF - Blood
IS - 14
ER -