Pathogenesis of SCID-X Gene Therapy - Induced Leukemias

SCID-X 基因治疗的发病机制 - 诱发白血病

• 批准号: 7878805
• 负责人: Utpal P Dave
• 金额: $ 12.72万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-14 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878805
• 关键词: Acceleration; Acute Megakaryocytic Leukemias; Affect; Aftercare; Age; Animals; Bacterial Infections; Biological Assay; Bone Marrow; Bone Marrow Transplantation; Clinical Trials; Cytokine Receptors; Data; Development; Disease; Foundations; Gene Transduction Agent; Gene Transfer; Genes; Genetic; Hematologic Neoplasms; Hematology; Hematopoietic stem cells; Human; IL2RG gene; Incidence; Insertional Activations; Insertional Mutagenesis; Integral Membrane Protein; Interleukin 2 Receptor Gamma; JAK3 gene; Ligands; Mature T-Lymphocyte; Mentored Clinical Scientist Development Award (K08); Modeling; Monitor; Mus; Mutation; Oncogenes; Oncogenic; Onset of illness; Pathogenesis; Pathway interactions; Patients; Principal Investigator; Protein Tyrosine Kinase; Protocols documentation; Research; Research Personnel; Retroviral Vector; Retroviridae; Signal Transduction; Site; T-Cell Leukemia; T-Lymphocyte; Testing; Time; Transgenes; Transgenic Mice; Transgenic Organisms; Transplantation; Viral; Viral Vector; Work; X-Linked Severe Combined Immunodeficiency; abstracting; career; gene therapy; hematopoietic tissue; interleukin-15 receptor; leukemia; loss of function; mutant; overexpression; programs; promoter; retroviral transduction; transcription factor; tumor

DESCRIPTION (provided by applicant): The research objective of this proposal is to test the functional cooperativity of the common gamma chain (IL2RG) and the LIM-Only 2 (LMO2) oncogene in leukemia induction. The proposal builds upon the Pi's postdoctoral work where retroviral insertional mutagenesis models were used to show that H2rg is a frequent site of insertion in Lmo2-induced T-cell leukemias. The results provide genetic evidence for cooperativity between these two genes and suggest an explanation for the high incidence of leukemia in the French gene therapy trial of X-linked severe combined immunodeficiency (SCID-X). The model suggests that the affected patients developed leukemia because of two "hits", insertional activation of LMO2 by the gene therapy vector and constitutive expression of the IL2RG transgene. The following specific aims will formally test this concept: (l)Transgenic mice overexpressing IL2RG will be constructed and followed for the development of leukemia; (2) IL2RG transgenics will be interbred with Cd2-Lmo2 transgenic mice to make bitransgenic mice overexpressing both genes. These mice will be followed and monitored for disease and compared with single transgenic littermate controls. Lmo2 transgenic mice develop T-cell leukemia with a median latency of 200 days, and so doubly transgenic mice, overexpressing both Lmo2 and IL2RG genes would be predicted to develop disease with shorter latency and/or higher incidence; and (3) genes within the IL2RG pathway will be tested for their ability to cooperate with Lmo2 in leukemia induction. StatSb transgenic mice will be interbred with Cd2-l_mo2 transgenics to create bitransgenics to be monitored as in Aim 2; and, cooperativity with constitutively active JAK3 will be explored using retroviral transduction of bone marrow. Confirmation of Lmo2/ll2rg cooperativity in gene therapy-induced leukemias has broad implications for the field of gene therapy, the treatment of SCID-X, and also the pathogenesis of sporadic T-cell leukemia. This Mentored Clinical Scientist Development Award will give the Principal Investigator protected time to pursue this important research and establish a foundation for an independent and productive career in academic Hematology. (End of Abstract)

描述（由申请人提供）： 本提案的研究目的是测试共同伽马链 (IL2RG) 和 LIM-Only 2 (LMO2) 癌基因在白血病诱导中的功能协同性。该提案以 Pi 的博士后工作为基础，其中使用逆转录病毒插入诱变模型表明 H2rg 是 Lmo2 诱导的 T 细胞白血病中的常见插入位点。这些结果为这两个基因之间的协同作用提供了遗传证据，并为法国 X 连锁严重联合免疫缺陷 (SCID-X) 基因治疗试验中白血病的高发病率提供了解释。该模型表明，受影响的患者因两次“命中”而患上白血病，即基因治疗载体对 LMO2 的插入激活和 IL2RG 转基因的组成型表达。以下具体目标将正式检验这一概念：（l）构建过表达IL2RG的转基因小鼠，并跟踪其发展为白血病； (2)将IL2RG转基因小鼠与Cd2-Lmo2转基因小鼠杂交，形成同时过表达两种基因的双转基因小鼠。将跟踪并监测这些小鼠的疾病情况，并与单个转基因同窝对照小鼠进行比较。 Lmo2 转基因小鼠患上 T 细胞白血病的潜伏期中位数为 200 天，因此过表达 Lmo2 和 IL2RG 基因的双转基因小鼠预计会患上潜伏期更短和/或发病率更高的疾病； (3)将测试IL2RG通路内的基因与Lmo2协同诱导白血病的能力。 StatSb转基因小鼠将与Cd2-1_mo2转基因小鼠杂交以产生将如目标2中那样进行监测的双转基因小鼠；并且，将使用骨髓逆转录病毒转导来探索与组成型活性 JAK3 的协同作用。 Lmo2/ll2rg 在基因治疗诱发的白血病中的协同作用的确认对于基因治疗领域、SCID-X 的治疗以及散发性 T 细胞白血病的发病机制具有广泛的意义。该指导临床科学家发展奖将为首席研究员提供受保护的时间来进行这项重要的研究，并为学术血液学领域的独立和富有成效的职业生涯奠定基础。 （摘要完）