Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms

Nils H. Thoennissen, Utz O. Krug, Dhong Hyun Tony Lee, Norihiko Kawamata, Gabriela B. Iwanski, Terra Lasho, Tamara Weiss, Daniel Nowak, Maya Koren-Michowitz, Motohiro Kato, Masashi Sanada, Lee Yung Shih, Arnon Nagler, Sophie D. Raynaud, Carsten Müller-Tidow, Ruben Mesa, Torsten Haferlach, D. Gary Gilliland, Ayalew Tefferi, Seishi OgawaH. Phillip Koeffler

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2882-2890
Number of pages9
JournalBlood
Volume115
Issue number14
DOIs
StatePublished - Apr 8 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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