Review: Oncogenic Insertional Mutagenesis as a Consequence of Retroviral Gene Therapy for X-Linked Severe Combined Immunodeficiency Disease.

For X-linked severe combined immunodeficiency (SCID-X1), the practice of gene therapy has revealed an unusual effect: insertional mutagenesis that can lead to leukemia. Even though incorporation of the retrovirus close to the oncogene for T-cell acute lymphoblastic leukemia (T-ALL), LIM-only protein 2 (LMO2) is observed frequently, but it is not clear why LMO2 expression is affected. It was demonstrated that in all the typical T-ALL oncogenes, there is mainly transcription of LMO2 in CD34+ progenitor cells. LYL1, TAN1, and TAL1 are very important intensification factors that are classically used in the gene therapy for copying LMO2 when they are stimulated. For this reason, oncogenes are susceptible to amalgamation with viruses. The IL-2R-gamma (IL-2 receptor γ chain) was found to be a supporting oncogene to LMO2. Nevertheless it was illustrated that excessive expression of IL-2R-gamma did not affect T-cell growth. In comparison to it, the excessive expression of LMO2 in CD34+ cells can cause ongoing increases in the development of T cells. Conversely, there is no effect on the development of B cells and myeloid cells. This information helps explain why LMO2 is mostly affected by various identified T-ALL oncogenes. In addition, throughout the process of T-cell development, expression of IL2R-gamma mediated by retrovirus may not always be oncogenic. As an alternative, replacement of signals of common IL-7 receptors may increase development of T cells wherever LMO2 was expressed and caused abnormal thymocyte development.