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Pathogenesis of SCID-X Gene Therapy - Induced Leukemias

SCID-X 基因治疗的发病机制 - 诱发白血病

基本信息

批准号：
8099490
负责人：
Utpal P Dave
金额：
$ 12.77万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
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/8099490
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 STAT5A gene Signal Transduction Site T-Cell Leukemia T-Lymphocyte Testing Time Transgenes Transgenic Mice Transgenic Organisms Transplantation Viral Vector Virus Diseases 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

项目摘要

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）：本研究的目的是检测共同γ链（IL 2 RG）和LIM-Only 2（LMO 2）癌基因在白血病诱导中的功能协同性。该提案建立在Pi的博士后工作的基础上，其中逆转录病毒插入诱变模型被用于表明H2 rg是Lmo 2诱导的T细胞白血病中的常见插入位点。这些结果提供了遗传学证据，这两个基因之间的协同性，并提出了一个解释白血病的高发病率在法国的基因治疗试验的X连锁严重联合免疫缺陷（SCID-X）。该模型表明，受影响的患者由于两个“命中”而发展成白血病，即基因治疗载体对LMO 2的插入激活和IL 2 RG转基因的组成型表达。以下具体目标将正式测试这一概念：（1）将构建过表达IL 2 RG的转基因小鼠，并跟踪白血病的发展;（2）将IL 2 RG转基因小鼠与Cd 2-Lmo 2转基因小鼠杂交，以制备过表达两种基因的双转基因小鼠。将对这些小鼠进行随访和疾病监测，并与单转基因同窝对照小鼠进行比较。Lmo 2转基因小鼠发展T细胞白血病，中位潜伏期为200天，因此过表达Lmo 2和IL 2 RG基因的双转基因小鼠将被预测发展具有较短潜伏期和/或较高发病率的疾病;和（3）将测试IL 2 RG途径内的基因在白血病诱导中与Lmo 2合作的能力。将StatSb转基因小鼠与Cd 2-l_mo2转基因小鼠杂交以产生双转基因小鼠，以如目的2中监测;并且，将使用骨髓的逆转录病毒转导来探索与组成型活性JAK 3的协同性。Lmo 2/ll 2 rg在基因治疗诱导的白血病中的协同性的确认对于基因治疗、SCID-X的治疗以及散发性T细胞白血病的发病机制的领域具有广泛的意义。该指导临床科学家发展奖将为主要研究者提供受保护的时间来进行这项重要的研究，并为学术血液学的独立和富有成效的职业生涯奠定基础。 (End摘要）