Murine Leukemias with Retroviral Insertions at Lmo2 Are Predictive of the Leukemias Induced in SCID-X1 Patients Following Retroviral Gene Therapy
Murine Leukemias with Retroviral Insertions at Lmo2 Are Predictive of the Leukemias Induced in SCID-X1 Patients Following Retroviral Gene Therapy
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DOI：
10.1371/journal.pgen.1000491
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发表时间：
2009-05-01
期刊：
影响因子：
4.5
通讯作者：
Copeland, Neal G.
中科院分区：
文献类型：
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作者：
Dave, Utpal P.;Akagi, Keiko;Copeland, Neal G.
五个X连锁严重联合免疫缺陷患者（SCID-X1）成功治疗自体骨髓干细胞感染离体IL 2 RG的逆转录病毒，随后发展为T细胞白血病和四个包含插入突变LMO 2。遗传证据还表明IL 2 RG在肿瘤形成中发挥作用，尽管这仍然存在争议。在这里，我们表明，在小鼠白血病与逆转录病毒插入LMO 2的基因和信号通路失调与人类白血病与LMO 2高表达的失调是相似的，是高度预测的白血病诱导的SCID-X1患者。我们还提供了额外的证据支持IL 2 RG和LMO 2在白血病诱导中合作的概念，但这是不够的，需要额外的合作突变。引起小鼠和人类白血病Lmo 2突变的遗传事件的高度一致性对于那些希望使用小鼠来模拟人类癌症的人来说是一个令人鼓舞的迹象，并且可能有助于设计更安全的逆转录病毒基因治疗方法。
Five X-linked severe combined immunodeficiency patients (SCID-X1) successfully treated with autologous bone marrow stem cells infected ex vivo with an IL2RG-containing retrovirus subsequently developed T-cell leukemia and four contained insertional mutations at LMO2. Genetic evidence also suggests a role for IL2RG in tumor formation, although this remains controversial. Here, we show that the genes and signaling pathways deregulated in murine leukemias with retroviral insertions at Lmo2 are similar to those deregulated in human leukemias with high LMO2 expression and are highly predictive of the leukemias induced in SCID-X1 patients. We also provide additional evidence supporting the notion that IL2RG and LMO2 cooperate in leukemia induction but are not sufficient and require additional cooperating mutations. The highly concordant nature of the genetic events giving rise to mouse and human leukemias with mutations at Lmo2 are an encouraging sign to those wanting to use mice to model human cancer and may help in designing safer methods for retroviral gene therapy.