Thymic precursor cells generate acute myeloid leukemia in NUP98-PHF23/NUP98-HOXD13 double transgenic mice
Thymic precursor cells generate acute myeloid leukemia in NUP98-PHF23/NUP98-HOXD13 double transgenic mice
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DOI：
10.1038/s41598-019-53610-7
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发表时间：
2019-11-20
影响因子：
4.6
通讯作者：
Aplan, Peter D.
中科院分区：
文献类型：
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作者：
Kundu, Subhadip;Park, Eun Sil;Aplan, Peter D.
在造血室中表达 NUP98-PHF23 (NP23) 或 NUP98-HOXD13 (NHD13) 融合的转基因小鼠在 9-14 个月大时会患上多种白血病，包括骨髓性白血病、红细胞性白血病、巨核细胞性白血病和淋巴性白血病。 NP23-NHD13双转基因小鼠是通过NP23和NHD13小鼠杂交产生的。值得注意的是，100%的NP23-NHD13双转基因小鼠在三个月内发展为急性髓系白血病(AML)，其特征是胸腺被白血病成髓细胞取代。胸腺的显着浸润导致了一个有趣的假设，即 NP23-NHD13 小鼠中产生的 AML 出现在胸腺中，而不是骨髓 (BM)。从白血病 NHD13/NP23 小鼠移植 CD4-CD8 双阴性 (DN) 胸腺细胞（Mac1 和 Gr1 阴性）证明 DN 胸腺细胞可以传播 AML，有限稀释研究表明，与 BM 相比，胸腺中的白血病起始细胞增加了 14 倍。进一步的胸腺细胞分级分离表明，DN1 和 DN2（而非 DN3 或 DN4）组分可传播 AML，并且 NP23-NHD13 小鼠胸腺中的 Lineage-Sca1 + Kit + (LSK) 细胞显着扩增（100 倍）。综上所述，这些结果表明 NP23-NHD13 小鼠的胸腺充当 AML 起始细胞的储存库，并且胸腺祖细胞可以传播 AML。
Transgenic mice that express either a NUP98-PHF23 (NP23) or NUP98-HOXD13 (NHD13) fusion in the hematopoietic compartment develop a wide spectrum of leukemias, including myeloid, erythroid, megakaryocytic and lymphoid, at age 9-14 months. NP23-NHD13 double transgenic mice were generated by interbreeding NP23 and NHD13 mice. Remarkably, 100% of the NP23-NHD13 double transgenic mice developed acute myeloid leukemia (AML) within three months, characterized by replacement of the thymus with leukemic myeloblasts. The marked infiltration of thymus led to the intriguing hypothesis that AML generated in NP23-NHD13 mice arose in the thymus, as opposed to the bone marrow (BM). Transplantation of CD4-CD8-double negative (DN) thymocytes (which were also negative for Mac1 and Gr1) from leukemic NHD13/NP23 mice demonstrated that DN thymocytes could transmit AML, and limiting dilution studies showed that leukemia initiating cells were increased 14-fold in the thymus compared to BM. Further thymocyte fractionation demonstrated that DN1 and DN2, but not DN3 or DN4 fractions transmitted AML, and a marked expansion (100-fold) of Lineage-Sca1 + Kit + (LSK) cells in the thymus of the NP23-NHD13 mice. Taken together, these results show that the thymus of NP23-NHD13 mice acts as a reservoir for AML initiating cells and that thymic progenitors can transmit AML.