Murine Leukemias with Insertional Mutations at Lmo2 Are Highly Predicitive of Leukemias Induced Following Gene Therapy in SCID-X1 Patients

Five SCID-X1 patients successfully treated with autologous bone marrow stem cells infected ex vivo with an IL2RG-containing retrovirus subsequently developed T-cell leukemia and four contained insertional mutations at LMO2, a known T cell oncogene. Indirect genetic evidence suggests a role for deregulated IL2RG expressed from the retroviral vector in tumor formation, although this remains controversial. Here we show that the genes and signaling pathways deregulated in murine leukemias with retroviral insertions at Lmo2 are strikingly similar to those in human leukemias with deregulated LMO2 and are highly predictive of the leukemias induced following gene therapy in SCID-X1 patients. We also provide genetic evidence suggesting that deregulated IL2RG and LMO2 expression cooperate to induce leukemia but are not sufficient and require additional cooperating mutations. The highly concordant nature of the genetic events giving rise to mouse and human leukemias with mutations at Lmo2 are an encouraging sign to those wanting to use mice to model human cancer and may help in designing safer methods for retroviral gene therapy.