PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia
PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia
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DOI：
10.1038/cdd.2015.159
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发表时间：
2016-06-01
影响因子：
12.4
通讯作者：
Curtis, D. J.
中科院分区：
文献类型：
--
作者：
Guirguis, A. A.;Slape, C. I.;Curtis, D. J.
骨髓增生异常综合征（MDS）的特点是造血功能低下，导致细胞减少。细胞凋亡增加和祖细胞功能异常被认为是导致这种表型的原因。与其他恶性肿瘤的情况一样，克服细胞凋亡被认为在急性髓性白血病（AML）的进展中很重要。使用NUP98-HOXD13 （NHD13）转基因MDS小鼠模型，我们之前报道过表达抗凋亡蛋白BCL2，阻断细胞凋亡和改善细胞减少，相反，延缓白血病进展。为了进一步理解这一令人惊讶的结果，我们研究了p53及其促凋亡效应物PUMA和NOXA在NHD13小鼠中的作用。p53或PUMA的缺失而NOXA的缺失减少了细胞凋亡，增加了mds再生细胞的数量。尽管对细胞凋亡和细胞数量有类似的影响，但p53和PUMA的缺失对AML的进展有着截然相反的影响：p53的缺失加速了白血病的进展，而PUMA的缺失显著延缓了白血病的进展。这可以部分解释为细胞对DNA损伤的不同反应。p53缺失导致更高水平的γ - h2ax（表明持续的DNA损伤），而puma缺失的NHD13祖细胞以与野生型细胞相当的方式解决DNA损伤。这些结果表明，靶向PUMA可能会改善MDS的细胞减少而不会对白血病进展产生不利影响，因此值得进一步研究。
Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with resultant cytopenias. Increased apoptosis and aberrantly functioning progenitors are thought to contribute to this phenotype. As is the case for other malignancies, overcoming apoptosis is believed to be important in progression toward acute myeloid leukemia (AML). Using the NUP98-HOXD13 (NHD13) transgenic mouse model of MDS, we previously reported that overexpression of the anti-apoptotic protein BCL2, blocked apoptosis and improved cytopenias, paradoxically, delaying leukemic progression. To further understand this surprising result, we examined the role of p53 and its pro-apoptotic effectors, PUMA and NOXA in NHD13 mice. The absence of p53 or PUMA but not NOXA reduced apoptosis and expanded the numbers of MDS-repopulating cells. Despite a similar effect on apoptosis and cell numbers, the absence of p53 and PUMA had diametrically opposed effects on progression to AML: absence of p53 accelerated leukemic progression, while absence of PUMA significantly delayed progression. This may be explained in part by differences in cellular responses to DNA damage. The absence of p53 led to higher levels of gamma-H2AX (indicative of persistent DNA lesions) while PUMA-deficient NHD13 progenitors resolved DNA lesions in a manner comparable to wild-type cells. These results suggest that targeting PUMA may improve the cytopenias of MDS without a detrimental effect on leukemic progression thus warranting further investigation.