Pathogenesis of SCID-X Gene Therapy - Induced Leukemias

描述(由申请人提供)： 该建议的研究目的是测试共同伽玛链(IL2RG)和LIM-Only-2(LMO2)癌基因在诱导白血病过程中的功能协同性。该建议建立在PI的博士后工作基础上，在那里，使用逆转录病毒插入突变模型来证明在Lmo2诱导的T细胞白血病中，H_2rg是一个频繁的插入位置。这些结果为这两个基因之间的协同性提供了遗传学证据，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，受影响的患者发生白血病是由于两种“命中”，即基因治疗载体插入激活LMO2和IL2RG转基因的结构性表达。以下具体目标将正式检验这一概念：(L)将构建和跟踪过度表达IL2RG的转基因小鼠，用于白血病的发展；(2)IL2RG转基因小鼠将与CD2-Lmo2转基因小鼠杂交，使双转基因小鼠同时过度表达这两个基因。将对这些小鼠进行跟踪和疾病监测，并与单一转基因小鼠对照进行比较。Lmo2转基因小鼠发生T细胞白血病的平均潜伏期为200天，因此，同时过度表达Lmo2和IL2RG基因的双转基因小鼠将被预测患上潜伏期更短和/或发病率更高的疾病；以及(3)IL2RG途径中的基因将被测试其与Lmo2协同诱导白血病的能力。STATSB转基因小鼠将与CD2-L_mo2转基因小鼠杂交，以创建要监测的双转基因基因；并将通过骨髓逆转录病毒转导来探索与固有活性JAK3的协同作用。证实Lmo2/Ll2Rg在基因治疗诱导的白血病中的协同作用，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具有广泛的意义。这项指导临床科学家发展奖将给予首席研究员受保护的时间来从事这项重要的研究，并为在学术血液学领域独立和富有成效的职业生涯奠定基础。 (摘要结束)

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)