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

来源：

BLOOD | 2010年 / 115卷 / 14期

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

页码：2882 / 2890

页数：9

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