LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1

被引：2714

作者：

Hacein-Bey-Abina, S

Von Kalle, C

Schmidt, M

McCcormack, MP

Wulffraat, N

Leboulch, P

Lim, A

Osborne, CS

Pawliuk, R

Morillon, E

Sorensen, R

Forster, A

Fraser, P

Cohen, JI

de Saint Basile, G

Alexander, I

Wintergerst, U

Frebourg, T

Aurias, A

Stoppa-Lyonnet, D

Romana, S

Radford-Weiss, I

Gross, F

Valensi, F

Delabesse, E

Macintyre, E

Sigaux, F

Soulier, J

Leiva, LE

Wissler, M

Prinz, C

Rabbitts, TH

Le Deist, F

Fischer, A ^{[1
]}

Cavazzana-Calvo, M

机构：

[1] INSERM, U429, F-75743 Paris 15, France

[2] Assistance Publ Hop Paris, Dept Biotherapie, F-75743 Paris, France

[3] Univ Paris 05, Lab Cytogenet, F-75743 Paris 15, France

[4] Univ Paris 05, Lab Cent Hematol, F-75743 Paris 15, France

[5] Univ Paris 05, CNRS, Unite Rech Associee 1461, F-75743 Paris 15, France

[6] Hop Necker Enfants Malad, Unite Immunol & Hematol Pediat, F-75743 Paris 15, France

[7] Univ Freiburg, Inst Mol Med & Cell Res, Freiburg, Germany

[8] Childrens Hosp Res Fdn, Cincinnati, OH 45229 USA

[9] MRC, Mol Biol Lab, Cambridge CB2 2QH, England

[10] Univ Med Ctr Utrecht, Wilhelmina Kinderziekenhuis, Utrecht, Netherlands

[11] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[12] Harvard Univ, Sch Med, Boston, MA 02115 USA

[13] INSERM, U277, F-75730 Paris, France

[14] Babraham Inst, Lab Chromatin & Gene Express, Dev Genet Programme, Cambridge CB2 4AT, England

[15] Louisiana State Univ, Hlth Sci Ctr, Dept Pediat, New Orleans, LA 70112 USA

[16] Childrens Hosp, New Orleans, LA 70112 USA

[17] NIAID, Med Virol Sect, Clin Invest Lab, Bethesda, MD 20892 USA

[18] Childrens Hosp Westmead, Sydney, NSW 2145, Australia

[19] Univ & Childrens Hosp, D-80337 Munich, Germany

[20] CHU, Serv Genet, F-76183 Rouen, France

[21] Fac Med & Pharm, INSERM 9906, Equipe Mixte, F-76183 Rouen, France

[22] Inst Curie, INSERM, U434, Paris 15, France

[23] Inst Curie, Dept Oncol Genet, Paris 15, France

[24] Hop St Louis, INSERM, U462, Paris, France

来源：

SCIENCE | 2003年 / 302卷 / 5644期

关键词：

D O I：

10.1126/science.1088547

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gammac) deficiency] in 9 out of 10 patients by retrovirus-mediated gammac gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.

引用

页码：415 / 419

页数：5

共 38 条

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