HSPA9/mortalin抑制通过TP53依赖机制破坏人CD34+造血祖细胞的红细胞成熟。

IF 3.3 3区 生物学 Q3 CELL BIOLOGY
Christopher Butler , Morgan Dunmire , Jaebok Choi , Gabor Szalai , Anissa Johnson , Wei Lei , Xin Chen , Liang Liu , Wei Li , Matthew J. Walter , Tuoen Liu
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引用次数: 0

摘要

骨髓增生异常综合征(MDS)是一组异质性克隆性造血干细胞恶性肿瘤,以造血细胞成熟异常、骨髓细胞凋亡增加和贫血为特征。它们是美国成年人中最常见的骨髓性血癌。目前还不完全清楚导致 MDS 表型或临床症状的全部基因突变。约10%-25%的MDS患者在5号染色体长臂上存在间隙性杂合子缺失[del(5q)],导致包括HSPA9在内的大量基因单倍性缺失。HSPA9 基因编码蛋白 mortalin,这是一种高度保守的热休克蛋白,主要定位于线粒体。我们之前的研究表明,敲除 HSPA9 可诱导人 CD34+ 造血祖细胞发生 TP53 依赖性凋亡。在本研究中,我们利用人体 CD34+ 细胞探讨了 HSPA9 在调节红细胞成熟中的作用。我们采用基因敲除和药物抑制的方法抑制了 HSPA9 的表达,结果发现抑制 HSPA9 会破坏 CD34+ 细胞中的红细胞成熟以及增加 p53 的表达。为了检验HSPA9调控红细胞成熟的分子机制是否依赖于TP53,我们在人CD34+细胞中单独或联合敲除了HSPA9和TP53。我们发现,敲除 TP53 可部分修复 HSPA9 敲除诱导的红细胞成熟缺陷,这表明 HSPA9 表达减少的细胞的红细胞成熟缺陷是 TP53 依赖性的。总之,这些研究结果表明,HSPA9水平的降低可能是TP53活化导致del(5q)相关MDS患者贫血的原因之一。意义声明:MDS 是美国最常见的成人骨髓性血癌。MDS 患者的典型症状包括疲劳,并与贫血相关。一些 MDS 患者携带 del(5q),包括 HSPA9 在内的一系列基因存在单倍性缺 陷。我们发现,抑制 HSPA9 会通过 TP53 依赖性机制破坏人类 CD34+ 造血祖细胞的红细胞成熟。我们的研究结果不仅表明,HSPA9水平的降低可能是del(5q)相关MDS患者贫血的原因之一,而且还为贫血的潜在机制提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

HSPA9/mortalin inhibition disrupts erythroid maturation through a TP53-dependent mechanism in human CD34+ hematopoietic progenitor cells

HSPA9/mortalin inhibition disrupts erythroid maturation through a TP53-dependent mechanism in human CD34+ hematopoietic progenitor cells

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies characterized by abnormal hematopoietic cell maturation, increased apoptosis of bone marrow cells, and anemia. They are the most common myeloid blood cancers in American adults. The full complement of gene mutations that contribute to the phenotypes or clinical symptoms in MDS is not fully understood. Around 10%–25% of MDS patients harbor an interstitial heterozygous deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes, including HSPA9. The HSPA9 gene encodes for the protein mortalin, a highly conserved heat shock protein predominantly localized in mitochondria. Our prior study showed that knockdown of HSPA9 induces TP53-dependent apoptosis in human CD34+ hematopoietic progenitor cells. In this study, we explored the role of HSPA9 in regulating erythroid maturation using human CD34+ cells. We inhibited the expression of HSPA9 using gene knockdown and pharmacological inhibition and found that inhibition of HSPA9 disrupted erythroid maturation as well as increased expression of p53 in CD34+ cells. To test whether the molecular mechanism of HSPA9 regulating erythroid maturation is TP53-dependent, we knocked down HSPA9 and TP53 individually or in combination in human CD34+ cells. We found that the knockdown of TP53 partially rescued the erythroid maturation defect induced by HSPA9 knockdown, suggesting that the defect in cells with reduced HSPA9 expression is TP53-dependent. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to the anemia observed in del(5q)-associated MDS patients due to the activation of TP53.

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来源期刊
Cell Stress & Chaperones
Cell Stress & Chaperones 生物-细胞生物学
CiteScore
7.60
自引率
2.60%
发文量
59
审稿时长
6-12 weeks
期刊介绍: Cell Stress and Chaperones is an integrative journal that bridges the gap between laboratory model systems and natural populations. The journal captures the eclectic spirit of the cellular stress response field in a single, concentrated source of current information. Major emphasis is placed on the effects of climate change on individual species in the natural environment and their capacity to adapt. This emphasis expands our focus on stress biology and medicine by linking climate change effects to research on cellular stress responses of animals, micro-organisms and plants.
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