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

Abstract

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⁻ CD8⁻ 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.

ACKNOWLEDGMENTS

This work was supported by the Medical Research Council and M.P.M. was funded by the Leukemia Research Fund (United Kingdom).

We thank James Cruickshank, Lynn Grift, Gareth King, Theresa Langford, Angela Middleton, Claire Pearce, and Charlotte Rickett for animal husbandry, Annette Lenton for production of the art work, and N. Lobato for commenting on the manuscript. We thank J. Roes and K. Rajewsky for the CD19-Cre-tk plasmid, X. Gu and K. Rajewsky for the Cre plasmid, and R. Perlmutter for the Lck transgenic cassette.