The LMO2 T-cell oncogene is activated via chromosomal translocations or retroviral insertion during gene therapy but has no mandatory role in normal T-cell development.
The LMO2 gene encodes a LIM-only protein and is a target of chromosomal translocations in human T-cell leukemia. Recently, two X-SCID patients treated by gene therapy to rescue T-cell lymphopoiesis developed T-cell leukemias with retroviral insertion into the LMO2 gene causing clonal T-cell proliferation. In view of the specificity of LMO2 in T-cell tumorigenesis, we investigated a possible role for Lmo2 in T-lymphopoiesis, using conditional knockout of mouse Lmo2 with loxP-flanked Lmo2 and Cre recombinase alleles driven by the promoters of the lymphoid-specific genes Rag1, CD19, and Lck. While efficient deletion of Lmo2 was observed, even in the earliest detectable lymphoid cell progenitors of the bone marrow, there was no disturbance of lymphopoiesis in either T- or B-cell lineages, and in contrast to Lmo2 transgenic mice, there were normal distributions of CD4- CD- thymocytes. We conclude that there is no mandatory role for LMO2 in lymphoid development, implying that its specific role in T-cell tumorigenesis results from a reprogramming of gene expression after enforced expression in T-cell precursors.
McCormack
Matthew P
MP
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom.
Forster
Alan
A
Drynan
Lesley
L
Pannell
Richard
R
Rabbitts
Terence H
TH
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006801:Humans; D060588:LIM Domain Proteins; D015458:Leukemia, T-Cell / Q000209:etiology / Q000235:genetics / Q000473:pathology; D038041:Lymphopoiesis / Q000235:genetics*; D008667:Metalloproteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009857:Oncogenes; D011518:Proto-Oncogene Proteins; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D014178:Translocation, Genetic
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; C513188:Lmo2 protein, mouse; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins; D004247:DNA