Control of AC133/CD133 and impact on human hematopoietic progenitor cells through nucleolin
Control of AC133/CD133 and impact on human hematopoietic progenitor cells through nucleolin
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DOI：
10.1038/leu.2015.146
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发表时间：
2015-11-01
期刊：
影响因子：
11.4
通讯作者：
Grinstein, E.
中科院分区：
文献类型：
--
作者：
Bhatia, S.;Reister, S.;Grinstein, E.
AC 133是CD 34+和CD 34-造血干/祖细胞（HSPC）亚群的主要表面标志物。AC 133 + HSPC具有高祖细胞活性，能够进行造血重建。此外，AC 133用于在几种血液恶性肿瘤中前瞻性分离肿瘤起始细胞。核仁素是一种多功能的肿瘤细胞生长因子，在某些血液肿瘤中具有异常活性，是肿瘤治疗的候选分子靶点。核仁素参与基因转录和RNA代谢，并且与分化的造血组织相反，在HSPC中优先表达。本研究通过核仁素与组织依赖性CD 133启动子P1的特异性相互作用，剖析了核仁素介导的表面AC 133及其同源基因CD 133的活化，作为对CD 34 + HSPC中AC 133表达至关重要的机制。在动员的外周血（MPB）来源的HSPCs，核仁素提高集落形成单位（CFU）的频率和丰富的粒细胞-巨噬细胞CFU。此外，核仁素扩增长期培养起始细胞，也促进造血祖细胞的长期、依赖于精氨酸的维持。MPB衍生的HSPC中的活性β-连环蛋白、活性Akt和Bcl 2水平是核仁素依赖性的，并且核仁素对这些细胞的作用部分依赖于β-连环蛋白活性。该研究为正常和恶性造血中干/祖细胞相关的分子网络提供了新的见解。
AC133 is a prominent surface marker of CD34+ and CD34- hematopoietic stem/progenitor cell (HSPC) subsets. AC133+ HSPCs contain high progenitor cell activity and are capable of hematopoietic reconstitution. Furthermore, AC133 is used for prospective isolation of tumor-initiating cells in several hematological malignancies. Nucleolin is a multifunctional factor of growing and cancer cells, which is aberrantly active in certain hematological neoplasms, and serves as a candidate molecular target for cancer therapy. Nucleolin is involved in gene transcription and RNA metabolism and is prevalently expressed in HSPCs, as opposed to differentiated hematopoietic tissue. The present study dissects nucleolin-mediated activation of surface AC133 and its cognate gene CD133, via specific interaction of nucleolin with the tissue-dependent CD133 promoter P1, as a mechanism that crucially contributes to AC133 expression in CD34+ HSPCs. In mobilized peripheral blood (MPB)-derived HSPCs, nucleolin elevates colony-forming unit (CFU) frequencies and enriches granulocyte-macrophage CFUs. Furthermore, nucleolin amplifies long-term culture-initiating cells and also promotes long-term, cytokine-dependent maintenance of hematopoietic progenitor cells. Active beta-catenin, active Akt and Bcl2 levels in MPB-derived HSPCs are nucleolin-dependent, and effects of nucleolin on these cells partially rely on beta-catenin activity. The study provides new insights into molecular network relevant to stem/progenitor cells in normal and malignant hematopoiesis.