LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1

S. Hacein-Bey-Abina; C. Von Kalle; M. Schmidt; M. P. McCormack; N. Wulffraat; P. Leboulch; A. Lim; C. S. Osborne; R. Pawliuk; E. Morillon; R. Sorensen; A. Forster; P. Fraser; J. I. Cohen; G. De Saint Basile; I. Alexander; U. Wintergerst; T. Frebourg; A. Aurias; D. Stoppa-Lyonnet; S. Romana; I. Radford-Weiss; F. Gross; F. Valensi; E. Delabesse; E. Macintyre; F. Sigaux; J. Soulier; L. E. Leiva; M. Wissler; C. Prinz; T. H. Rabbitts; F. Le Deist; A. Fischer; M. Cavazzana-Calvo

doi:10.1126/science.1088547

LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1

S. Hacein-Bey-Abina, C. Von Kalle, M. Schmidt, M. P. McCormack, N. Wulffraat, P. Leboulch, A. Lim, C. S. Osborne, R. Pawliuk, E. Morillon, R. Sorensen, A. Forster, P. Fraser, J. I. Cohen, G. De Saint Basile, I. Alexander, U. Wintergerst, T. Frebourg, A. Aurias, D. Stoppa-LyonnetS. Romana, I. Radford-Weiss, F. Gross, F. Valensi, E. Delabesse, E. Macintyre, F. Sigaux, J. Soulier, L. E. Leiva, M. Wissler, C. Prinz, T. H. Rabbitts, F. Le Deist, A. Fischer, M. Cavazzana-Calvo

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Abstract

We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as γ chain (γc) deficiency] in 9 out of 10 patients by retrovirus-mediated γc gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with γδ+ or αβ+ 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.

Original language	English
Pages (from-to)	415-419
Number of pages	5
Journal	Science
Volume	302
Issue number	5644
DOIs	https://doi.org/10.1126/science.1088547
Publication status	Published - 17 Oct 2003
Externally published	Yes

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Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., McCormack, M. P., Wulffraat, N., Leboulch, P., Lim, A., Osborne, C. S., Pawliuk, R., Morillon, E., Sorensen, R., Forster, A., Fraser, P., Cohen, J. I., De Saint Basile, G., Alexander, I., Wintergerst, U., Frebourg, T., Aurias, A., ... Cavazzana-Calvo, M. (2003). LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1. Science, 302(5644), 415-419. https://doi.org/10.1126/science.1088547

@article{c87e72e505124e528ea10cac986eb328,

title = "LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1",

abstract = "We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as γ chain (γc) deficiency] in 9 out of 10 patients by retrovirus-mediated γc gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with γδ+ or αβ+ 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.",

author = "S. Hacein-Bey-Abina and {Von Kalle}, C. and M. Schmidt and McCormack, {M. P.} and N. Wulffraat and P. Leboulch and A. Lim and Osborne, {C. S.} and R. Pawliuk and E. Morillon and R. Sorensen and A. Forster and P. Fraser and Cohen, {J. I.} and {De Saint Basile}, G. and I. Alexander and U. Wintergerst and T. Frebourg and A. Aurias and D. Stoppa-Lyonnet and S. Romana and I. Radford-Weiss and F. Gross and F. Valensi and E. Delabesse and E. Macintyre and F. Sigaux and J. Soulier and Leiva, {L. E.} and M. Wissler and C. Prinz and Rabbitts, {T. H.} and {Le Deist}, F. and A. Fischer and M. Cavazzana-Calvo",

year = "2003",

month = oct,

day = "17",

doi = "10.1126/science.1088547",

language = "English",

volume = "302",

pages = "415--419",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science (AAAS)",

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Hacein-Bey-Abina, S, Von Kalle, C, Schmidt, M, McCormack, 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 2003, 'LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1', Science, vol. 302, no. 5644, pp. 415-419. https://doi.org/10.1126/science.1088547

TY - JOUR

T1 - LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1

AU - Hacein-Bey-Abina, S.

AU - Von Kalle, C.

AU - Schmidt, M.

AU - McCormack, M. P.

AU - Wulffraat, N.

AU - Leboulch, P.

AU - Lim, A.

AU - Osborne, C. S.

AU - Pawliuk, R.

AU - Morillon, E.

AU - Sorensen, R.

AU - Forster, A.

AU - Fraser, P.

AU - Cohen, J. I.

AU - De Saint Basile, G.

AU - Alexander, I.

AU - Wintergerst, U.

AU - Frebourg, T.

AU - Aurias, A.

AU - Stoppa-Lyonnet, D.

AU - Romana, S.

AU - Radford-Weiss, I.

AU - Gross, F.

AU - Valensi, F.

AU - Delabesse, E.

AU - Macintyre, E.

AU - Sigaux, F.

AU - Soulier, J.

AU - Leiva, L. E.

AU - Wissler, M.

AU - Prinz, C.

AU - Rabbitts, T. H.

AU - Le Deist, F.

AU - Fischer, A.

AU - Cavazzana-Calvo, M.

PY - 2003/10/17

Y1 - 2003/10/17

N2 - We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as γ chain (γc) deficiency] in 9 out of 10 patients by retrovirus-mediated γc gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with γδ+ or αβ+ 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.

AB - We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as γ chain (γc) deficiency] in 9 out of 10 patients by retrovirus-mediated γc gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with γδ+ or αβ+ 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.

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U2 - 10.1126/science.1088547

DO - 10.1126/science.1088547

M3 - Article

C2 - 14564000

AN - SCOPUS:0142084745

SN - 0036-8075

VL - 302

SP - 415

EP - 419

JO - Science

JF - Science

IS - 5644

ER -

LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1

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