Fragile sites are preferential targets for integrations of MLV vectors in gene therapy

被引：39

作者：

Bester, A. C.

Schwartz, M.

Schmidt, M.

Garrigue, A.

Hacein-Bey-Abina, S.

Cavazzana-Calvo, M.

Ben-Porat, N.

Von Kalle, C.

Fischer, A.

Kerem, B. ^{[1
]}

机构：

[1] Hebrew Univ Jerusalem, Dept Genet, Silberman Life Sci Inst, IL-91904 Jerusalem, Israel

[2] Univ Freiburg, Inst Mol Med & cell Res, Dept Internal Med 1, Freiburg, Germany

[3] Lab Cytogenet, INSERM U429, Paris, France

[4] Assistance Publ Hop Paris, Dept Biotherapie, Paris, France

[5] Cincinnati Childrens Hosp, Res Fdn, Div Expt Hematol, Mol & GeneTherapy Program, Cincinnati, OH USA

[6] Hop Necker Enfants Malad, Unite Immunol & Hematol Pediat, Paris, France

来源：

GENE THERAPY | 2006年 / 13卷 / 13期

关键词：

fragile sites; viral integration; LMO2; leukemia;

D O I：

10.1038/sj.gt.3302752

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：

Following gene therapy of SCID-X1 using murine leukemia virus (MLV) derived vector, two patients developed leukemia owing to an activating vector integration near the LMO2 gene. We found that these integrations reside within FRA11E, a common fragile site known to correlate with chromosomal breakpoints in tumors. Further analysis showed that fragile sites attract a nonrandom number of MLV integrations, shedding light on its integration mechanism and risk-to-benefit ratio in gene therapy.

引用

收藏

页码：1057 / 1059

页数：3

相关论文

共 12 条

[1] Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease [J].

Cavazzana-Calvo, M ;

Hacein-Bey, S ;

Basile, CD ;

Gross, F ;

Yvon, E ;

Nusbaum, P ;

Selz, F ;

Hue, C ;

Certain, S ;

Casanova, JL ;

Bousso, P ;

Le Deist, F ;

Fischer, A .

SCIENCE, 2000, 288 (5466) :669-672

[2] DNA POLYMERASE-ALPHA INHIBITION BY APHIDICOLIN INDUCES GAPS AND BREAKS AT COMMON FRAGILE SITES IN HUMAN-CHROMOSOMES [J].

GLOVER, TW ;

BERGER, C ;

COYLE, J ;

ECHO, B .

HUMAN GENETICS, 1984, 67 (02) :136-142

[3] LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1 [J].

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 ;

Cavazzana-Calvo, M .

SCIENCE, 2003, 302 (5644) :415-419

[4] Replication delay along FRA7H, a common fragile site on human chromosome 7, leads to chromosomal instability [J].

Hellman, A ;

Rahat, A ;

Scherer, SW ;

Darvasi, A ;

Tsui, LP ;

Kerem, B .

MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (12) :4420-4427

[5]

Kaiser J, 2005, SCIENCE, V307, P1544

[6] Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction [J].

Le Beau, MM ;

Rassool, FV ;

Neilly, ME ;

Espinosa, R ;

Glover, TW ;

Smith, DI ;

McKeithan, TW .

HUMAN MOLECULAR GENETICS, 1998, 7 (04) :755-761

[7] Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences [J].

Mitchell, RS ;

Beitzel, BF ;

Schroder, ARW ;

Shinn, P ;

Chen, HM ;

Berry, CC ;

Ecker, JR ;

Bushman, FD .

PLOS BIOLOGY, 2004, 2 (08) :1127-1137

[8] SELECTIVE DEGRADATION OF INTEGRATED MURINE LEUKEMIA PROVIRAL DNA BY DEOXYRIBONUCLEASES [J].

PANET, A ;

CEDAR, H .

CELL, 1977, 11 (04) :933-940

[9] Genetic alterations in cancer as a result of breakage at fragile sites [J].

Popescu, NC .

CANCER LETTERS, 2003, 192 (01) :1-17

[10] Polyclonal long-term repopulating stem cell clones in a primate model [J].

Schmidt, M ;

Zickler, P ;

Hoffmann, G ;

Haas, S ;

Wissler, M ;

Muessig, A ;

Tisdale, JF ;

Kuramoto, K ;

Andrews, RG ;

Wu, T ;

Kiem, HP ;

Dunbar, CE ;

von Kalle, C .

BLOOD, 2002, 100 (08) :2737-2743