Development of a multi-step leukemogenesis model of MLL-rearranged leukemia using humanized mice.
Development of a multi-step leukemogenesis model of MLL-rearranged leukemia using humanized mice.
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DOI：
10.1371/journal.pone.0037892
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ishii N
中科院分区：
文献类型：
--
作者：
Moriya K;Suzuki M;Watanabe Y;Takahashi T;Aoki Y;Uchiyama T;Kumaki S;Sasahara Y;Minegishi M;Kure S;Tsuchiya S;Sugamura K;Ishii N
混合系白血病（MLL）融合癌基因与急性白血病和继发性治疗相关的急性白血病密切相关。为了了解MLL重排白血病，已经建立了几种这种疾病的小鼠模型。然而，源自小鼠造血干细胞（HSC）的小鼠白血病可能与人类白血病不完全可比。在这里，我们通过将转导MLL-AF 10癌基因的人脐带血来源的HSC移植到超免疫缺陷小鼠品系NOD/Shi-scid，IL-2 R γ−/−（NOG）小鼠中，开发了人白血病的人源化小鼠模型。将MLL-AF 10转导的HSC注射到NOG小鼠的肝脏中增强了多系造血，但不诱导白血病。因为ras基因的活性突变经常在MLL相关的白血病中发现，我们接下来将K-ras基因的组成型活性形式与MLL-AF 10癌基因一起转导。移植后8周，所有受体小鼠均发生急性单核细胞白血病（法国-美国-英国分类中的M5表型）。因此，我们成功地建立了一个人ML重排白血病，是在体内从人HSC。此外，由于单用突变K-ras基因的强制表达不足以诱导白血病的发生，本模型也可能为人类白血病的多步白血病发生模型提供一个有用的实验平台。
Mixed-lineage-leukemia (MLL) fusion oncogenes are intimately involved in acute leukemia and secondary therapy-related acute leukemia. To understand MLL-rearranged leukemia, several murine models for this disease have been established. However, the mouse leukemia derived from mouse hematopoietic stem cells (HSCs) may not be fully comparable with human leukemia. Here we developed a humanized mouse model for human leukemia by transplanting human cord blood-derived HSCs transduced with an MLL-AF10 oncogene into a supra-immunodeficient mouse strain, NOD/Shi-scid, IL-2Rγ−/− (NOG) mice. Injection of the MLL-AF10-transduced HSCs into the liver of NOG mice enhanced multilineage hematopoiesis, but did not induce leukemia. Because active mutations in ras genes are often found in MLL-related leukemia, we next transduced the gene for a constitutively active form of K-ras along with the MLL-AF10 oncogene. Eight weeks after transplantation, all the recipient mice had developed acute monoblastic leukemia (the M5 phenotype in French-American-British classification). We thus successfully established a human MLL-rearranged leukemia that was derived in vivo from human HSCs. In addition, since the enforced expression of the mutant K-ras alone was insufficient to induce leukemia, the present model may also be a useful experimental platform for the multi-step leukemogenesis model of human leukemia.
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