Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients.
X-linked SCID (SCID-X1) is amenable to correction by gene therapy using conventional gammaretroviral vectors. Here, we describe the occurrence of clonal T cell acute lymphoblastic leukemia (T-ALL) promoted by insertional mutagenesis in a completed gene therapy trial of 10 SCID-X1 patients. Integration of the vector in an antisense orientation 35 kb upstream of the protooncogene LIM domain only 2 (LMO2) caused overexpression of LMO2 in the leukemic clone. However, leukemogenesis was likely precipitated by the acquisition of other genetic abnormalities unrelated to vector insertion, including a gain-of-function mutation in NOTCH1, deletion of the tumor suppressor gene locus cyclin-dependent kinase 2A (CDKN2A), and translocation of the TCR-beta region to the STIL-TAL1 locus. These findings highlight a general toxicity of endogenous gammaretroviral enhancer elements and also identify a combinatorial process during leukemic evolution that will be important for risk stratification and for future protocol design.
Howe
Steven J
SJ
Centre for Immunodeficiency, Molecular Immunology Unit, UCL Institute of Child Health, University College London, London, United Kingdom.
Mansour
Marc R
MR
Schwarzwaelder
Kerstin
K
Bartholomae
Cynthia
C
Hubank
Michael
M
Kempski
Helena
H
Brugman
Martijn H
MH
Pike-Overzet
Karin
K
Chatters
Stephen J
SJ
de Ridder
Dick
D
Gilmour
Kimberly C
KC
Adams
Stuart
S
Thornhill
Susannah I
SI
Parsley
Kathryn L
KL
Staal
Frank J T
FJ
Gale
Rosemary E
RE
Linch
David C
DC
Bayford
Jinhua
J
Brown
Lucie
L
Quaye
Michelle
M
Kinnon
Christine
C
Ancliff
Philip
P
Webb
David K
DK
Schmidt
Manfred
M
von Kalle
Christof
C
Gaspar
H Bobby
HB
Thrasher
Adrian J
AJ
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology; D041321:Chromosomes, Human, X; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods*; D006801:Humans; D007223:Infant; D060588:LIM Domain Proteins; D008297:Male; D008667:Metalloproteins / Q000235:genetics; D008954:Models, Biological; D016296:Mutagenesis; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000209:etiology* / Q000628:therapy; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1 / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000628:therapy*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D008667:Metalloproteins; C497761:NOTCH1 protein, human; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D015375:Receptors, Interleukin-2