Oncogene iASPP enhances self-renewal of hematopoietic stem cells and facilitates their resistance to chemotherapy and irradiation
Oncogene iASPP enhances self-renewal of hematopoietic stem cells and facilitates their resistance to chemotherapy and irradiation
复制标题
癌基因 iASPP 增强造血干细胞的自我更新并促进其对化疗和放疗的抵抗力
DOI：
10.1096/fj.13-244632
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发表时间：
2014-07-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Jianxiang
中科院分区：
文献类型：
--
作者：
Jia, Yujiao;Peng, Leiwen;Wang, Jianxiang
iASPP是p53促凋亡蛋白（ASPP）家族的成员，负性调节p53的凋亡功能。在造血系统中，iASPP的过表达导致细胞凋亡的阻断，这可能在调节造血干细胞（HSC）数量中起作用。为了解决这个问题，我们首先分析了iASPP在急性白血病（AL）患者中的表达，发现它在AL患者中高度表达。我们进一步建立了人iASPP在造血细胞中特异性表达的转基因小鼠模型。iASPP的过表达导致长期HSC、短期HSC、多能祖细胞和共同髓系祖细胞的比例增加。iASPP转基因小鼠的HSC具有长期重建潜力的优势。此外，iASPP转基因小鼠的造血细胞表现出显著较低水平的p53依赖性凋亡。iASPP转基因小鼠造血细胞辐射损伤后γ-H2 AX表达水平较高，持续时间较长。这些结果提供了iASPP可以增加HSC群体和重建能力的第一个证据。有趣的是，在对细胞损伤刺激的反应中，iASPP可以保护造血细胞免于凋亡，同时这些抗凋亡细胞会有更多的突变积累，这可能是恶性转化的潜在风险。
iASPP is a member of the apoptosisstimulating proteins of p53 (ASPP) family and negatively regulates the apoptotic function of p53. In a hematopoietic system, overexpression of iASPP results in blockage of apoptosis, which may play a role in regulating hematopoietic stem cell (HSC) numbers. To address this, we first analyzed the expression of iASPP in patients with acute leukemia (AL) and found it was highly expressed in patients with AL. We further established a transgenic mouse model in which human iASPP was specifically expressed in hematopoietic cells. Overexpression of iASPP led to an increase in the proportion of long-term HSCs, short-term HSCs, multipotent progenitors, and common myeloid progenitor. HSCs from iASPP transgenic mice had an advantage in long-term reconstitution potential. In addition, the hematopoietic cells from iASPP transgenic mice exhibited a significantly lower level of p53 dependent apoptosis. After irradiation damage, hematopoietic cells of iASPP transgenic mice had a higher level of gamma-H2AX expression, which lasted for a longer time. These results provide the first evidence that the iASPP can increase HSC populations and reconstitution capacity. Interestingly, in response to cell damage stimuli, hematopoietic cells can be protected against apoptosis by iASPP; meanwhile these apoptosis-resistant cells would have more mutation accumulation, which might be the potential risk for malignant transformation.