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）： 该提案的研究目标是测试白血病诱导中普通伽马链（IL2RG）和lim-2（LMO2）癌基因的功能合作。该提案基于PI的博士后工作，其中使用逆转录病毒插入诱变模型来表明H2RG是LMO2诱导的T-Cell Leukemias的频繁插入部位。该结果为这两个基因之间的合作提供了遗传证据，并提出了对白血病高发病率的解释，在法国基因治疗试验的X连锁严重合并免疫缺陷试验（SCID-X）中。该模型表明，受影响的患者由于两个“命中”，基因治疗载体对LMO2的插入激活以及IL2RG转基因的本构表达而患有白血病。以下具体目的将正式检验以下概念：（l）将构建过表达IL2RG的转基因小鼠，并遵循白血病的发展； （2）IL2RG转基因将与CD2-LMO2转基因小鼠杂交，以使其表达过表达这两个基因的次基因小鼠。这些小鼠将被遵循并监测疾病，并将其与单个转基因同立立物物对照进行比较。 LMO2转基因小鼠会发展为200天的中位潜伏期的T细胞白血病，并且具有双重转基因小鼠，过表达LMO2和IL2RG基因将被预测会出现较短的潜伏期和/或更高的发病率； （3）IL2RG途径中的基因将测试其与白血病诱导中LMO2合作的能力。 STATSB转基因小鼠将与CD2-L_MO2转基因杂交，以创建像AIM 2一样监测的Bittransgenics；并且，将使用骨髓的逆转录转导与组成性活跃的JAK3合作。确认基因治疗诱导的白血病中LMO2/LL2RG合作性对基因治疗领域，SCID-X的治疗以及零星T细胞白血病的发病机理具有广泛的影响。这项受过指导的临床科学家发展奖将使主要研究人员受到保护的时间，以从事这项重要的研究，并为学术血液学独立和生产力的职业奠定基础。 （抽象的结尾）