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

被引:100
作者
Thoennissen, Nils H. [1 ]
Krug, Utz O. [2 ]
Lee, Dhong Hyun Tony [1 ]
Kawamata, Norihiko [1 ]
Iwanski, Gabriela B. [1 ]
Lasho, Terra [3 ]
Weiss, Tamara [4 ]
Nowak, Daniel [1 ]
Koren-Michowitz, Maya [1 ]
Kato, Motohiro [5 ,6 ,7 ,8 ]
Sanada, Masashi [5 ,6 ,7 ,8 ]
Shih, Lee-Yung [9 ]
Nagler, Arnon [10 ,11 ]
Raynaud, Sophie D. [12 ]
Mueller-Tidow, Carsten [2 ]
Mesa, Ruben [3 ]
Haferlach, Torsten [4 ]
Gilliland, D. Gary [13 ,14 ,15 ]
Tefferi, Ayalew [3 ]
Ogawa, Seishi [5 ,6 ,7 ,8 ]
Koeffler, H. Phillip [1 ,16 ]
机构
[1] Univ Calif Los Angeles, Sch Med, Cedars Sinai Med Ctr, Div Hematol & Oncol, Los Angeles, CA 90048 USA
[2] Univ Munster, Dept Med Hematol & Oncol, Munster, Germany
[3] Mayo Clin, Dept Hematol, Rochester, MN USA
[4] MLL, Munich, Germany
[5] Univ Tokyo, Grad Sch Med, Dept Hematol & Oncol, Tokyo, Japan
[6] Univ Tokyo, Grad Sch Med, Dept Cell Therapy & Transplantat Med, Tokyo, Japan
[7] Univ Tokyo, Grad Sch Med, 21st Century COE Program, Tokyo, Japan
[8] Japan Sci & Technol Agcy, Tokyo, Japan
[9] Chang Gung Univ, Chang Gung Mem Hosp, Dept Internal Med, Taiwan Sch Med,Div Hematol Oncol, Tao Yuan, Taiwan
[10] Tel Aviv Univ, Sheba Med Ctr, Div Hematol, IL-69978 Tel Aviv, Israel
[11] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel
[12] Archet Hosp, Genet Lab, Nice, France
[13] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA
[14] Harvard Stem Cell Inst, Boston, MA USA
[15] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA
[16] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore
基金
美国国家卫生研究院;
关键词
ACUTE MYELOID-LEUKEMIA; C-CBL; PRIMARY MYELOFIBROSIS; UNIPARENTAL DISOMY; QUANTITATIVE PCR; DISORDERS; MUTATIONS; JAK2; AML; LEUKEMOGENESIS;
D O I
10.1182/blood-2009-07-235119
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. (Blood. 2010; 115(14): 2882-2890)
引用
收藏
页码:2882 / 2890
页数:9
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