Ectopic retroviral expression of LMO2, but not IL2R gamma, blocks human T-cell development from CD34+cells: implications for leukemogenesis in gene therapy
| Autor: | Mjt Reinders, Martijn H. Brugman, Adrian J. Thrasher, Gerard Wagemaker, Miranda R. M. Baert, Denise T. D. de Ridder, J J M van Dongen, Monique M.A. Verstegen, Frank Jakob Theodor Staal, Floor Weerkamp, Steven J. Howe, Karin Pike-Overzet |
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| Přispěvatelé: | Immunology, Hematology |
| Rok vydání: | 2007 |
| Předmět: |
LMO2
Cancer Research T-Lymphocytes Antigens CD34 Biology medicine.disease_cause LYL1 Antigens CD hemic and lymphatic diseases Proto-Oncogene Proteins Metalloproteins medicine Humans Leukemia-Lymphoma Adult T-Cell Progenitor cell Growth Substances Adaptor Proteins Signal Transducing Severe combined immunodeficiency Leukemia Oncogene Receptors Interleukin-2 Hematology Genetic Therapy LIM Domain Proteins medicine.disease DNA-Binding Proteins Mutagenesis Insertional Retroviridae Oncology Cancer research Carcinogenesis TAL1 |
| Zdroj: | Leukemia, 21(4), 754-763. Nature Publishing Group |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | The occurrence of leukemia in a gene therapy trial for SCID-X1 has highlighted insertional mutagenesis as an adverse effect. Although retroviral integration near the T-cell acute lymphoblastic leukemia (T-ALL) oncogene LIM-only protein 2 (LMO2) appears to be a common event, it is unclear why LMO2 was preferentially targeted. We show that of classical T-ALL oncogenes, LMO2 is most highly transcribed in CD34+ progenitor cells. Upon stimulation with growth factors typically used in gene therapy protocols transcription of LMO2, LYL1, TAL1 and TAN1 is most prominent. Therefore, these oncogenes may be susceptible to viral integration. The interleukin-2 receptor gamma chain (IL2Rgamma), which is mutated in SCID-X1, has been proposed as a cooperating oncogene to LMO2. However, we found that overexpressing IL2Rgamma had no effect on T-cell development. In contrast, retroviral overexpression of LMO2 in CD34+ cells caused severe abnormalities in T-cell development, but B-cell and myeloid development remained unaffected. Our data help explain why LMO2 was preferentially targeted over many of the other known T-ALL oncogenes. Furthermore, during T-cell development retrovirus-mediated expression of IL2Rgamma may not be directly oncogenic. Instead, restoration of normal IL7-receptor signaling may allow progression of T-cell development to stages where ectopic LMO2 expression causes aberrant thymocyte growth. |
| Databáze: | OpenAIRE |
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