Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease

被引：624

作者：

Stein, Stefan ^{[1
]}

Ott, Marion G. ^{[2
]}

Schultze-Strasser, Stephan ^{[1
]}

Jauch, Anna ^{[3
]}

Burwinkel, Barbara ^{[4
,5
]}

Kinner, Andrea ^{[1
]}

Schmidt, Manfred ^{[6
]}

Kraemer, Alwin ^{[7
,8
]}

Schwaeble, Joachim ^{[2
]}

Glimm, Hanno ^{[6
]}

Koehl, Ulrike ^{[9
]}

Preiss, Carolin ^{[1
]}

Ball, Claudia ^{[6
]}

Martin, Hans ^{[2
]}

Goehring, Gudrun ^{[10
]}

Schwarzwaelder, Kerstin ^{[6
]}

Hofmann, Wolf-Karsten ^{[11
]}

Karakaya, Kadin ^{[7
,8
]}

Tchatchou, Sandrine ^{[4
,5
]}

Yang, Rongxi ^{[4
,5
]}

Reinecke, Petra ^{[12
]}

Kuehlcke, Klaus ^{[13
,14
]}

Schlegelberger, Brigitte ^{[10
]}

Thrasher, Adrian J. ^{[15
]}

Hoelzer, Dieter ^{[2
]}

Seger, Reinhard

von Kalle, Christof ^{[6
]}

Grez, Manuel ^{[1
]}

机构：

[1] Inst Biomed Res, Frankfurt, Germany

[2] Univ Med Sch, Dept Hematol Oncol, Frankfurt, Germany

[3] Univ Heidelberg Hosp, Inst Human Genet, Heidelberg, Germany

[4] German Canc Res Ctr, Mol Epidemiol Grp, D-6900 Heidelberg, Germany

[5] Univ Womens Clin, Div Mol Biol Breast Canc, Heidelberg, Germany

[6] Natl Ctr Tumor Dis, Dept Translat Oncol, Heidelberg, Germany

[7] German Canc Res Ctr, Clin Cooperat Unit Mol Hematol Oncol, D-6900 Heidelberg, Germany

[8] Heidelberg Univ, Dept Internal Med 5, Heidelberg, Germany

[9] Hannover Med Sch, Dept Cell & Mol Pathol, D-3000 Hannover, Germany

[10] Charite, Dept Hematol Oncol & Transfus Med, Berlin, Germany

[11] Univ Dusseldorf, Inst Pathol, D-4000 Dusseldorf, Germany

[12] EUFETS AG, Idar Oberstein, Germany

[13] UCL Inst Child Hlth, Ctr Immunodeficiency, London, England

[14] Great Ormond St Hosp Sick Children, London WC1N 3JH, England

[15] Univ Childrens Hosp Zurich, Div Hematol Immunol, Zurich, Switzerland

来源：

NATURE MEDICINE | 2010年 / 16卷 / 02期

基金：

英国惠康基金;

关键词：

SEVERE COMBINED IMMUNODEFICIENCY; RETROVIRAL VECTOR INSERTION; ACUTE MYELOID-LEUKEMIA; HEMATOPOIETIC-CELLS; EXPRESSION; METHYLATION; MLL5; PROLIFERATION; INTEGRATION; REPRESSION;

D O I：

10.1038/nm.2088

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.

引用

页码：198 / U105

页数：8

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