Induction of tumor arrest and differentiation with prolonged survival by intermittent hypoxia in a mouse model of acute myeloid leukemia
Induction of tumor arrest and differentiation with prolonged survival by intermittent hypoxia in a mouse model of acute myeloid leukemia
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DOI：
10.1182/blood-2005-03-1278
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发表时间：
2006-01-15
期刊：
影响因子：
20.3
通讯作者：
Chen, GQ
中科院分区：
文献类型：
--
作者：
Liu, W;Guo, M;Chen, GQ
我们以前发现，轻度的真实的缺氧和缺氧模拟剂诱导急性髓性白血病（AML）的体外细胞分化。我们在此研究了间歇性低氧对PML-RAR α转基因AML小鼠模型中白血病母细胞同基因移植物的体内影响。对于间歇性缺氧，白血病小鼠被安置在相当于海拔6000米的缺氧室中，每天连续18小时。结果表明，间歇性低氧显著延长了接受移植的白血病小鼠的存活时间，尽管它未能治愈这种疾病。通过组织学和细胞学分析，间歇性低氧显示出抑制白血病原始细胞在外周血、骨髓、脾和肝中的浸润，而不诱导凋亡。更有趣的是，间歇性缺氧也诱导白血病细胞进行分化，缺氧诱导因子-1 α蛋白的逐步增加，证明了成熟的髓样细胞的形态标准和小鼠髓样细胞分化相关抗原Gr-1和Mac-1的表达增加。总之，本研究代表了首次尝试表征缺氧对AML小鼠模型的体内影响。进一步的研究可能会发现以一种有益于AML患者的方式模拟缺氧的分化作用的方法。
We showed previously that mild real hypoxia and hypoxia-mimetic agents induced in vitro cell differentiation of acute myelold leukemia (AML). We here investigate the in vivo effects of intermittent hypoxia on syngenic grafts of leukemic blasts in a PML-RAR alpha transgenic mouse model of AML. For intermittent hypoxia, leukemic mice were housed in a hypoxia chamber equivalent to an altitude of 6000 m for 18 hours every consecutive day. The results show that intermittent hypoxia significantly prolongs the survival of the leukemic mice that received transplants, although it fails to cure the disease. By histologic and cytologic analyses, intermittent hypoxia is shown to inhibit the infiltration of leukemic blasts in peripheral blood, bone marrow, spleen, and liver without apoptosis induction. More intriguingly, intermittent hypoxia also induces leukemic cells to undergo differentiation with progressive increase of hypoxia-inducible factor-1 alpha protein, as evidenced by morphologic criteria of maturating myeloid cells and increased expression of mouse myeloid cell differentiation-related antigens Gr-1 and Mac-1. Taken together, this study represents the first attempt to characterize the in vivo effects of hypoxia on an AML mouse model. Additional investigations may uncover ways to mimic the differentiative effects of hypoxia in a manner that will benefit human patients with AML.