Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Transfusion. 2013 May;53(5):1037-49. doi: 10.1111/j.1537-2995.2012.03888.x. Epub 2012 Aug 31.
Stem cell factor SALL4 is a zinc finger transcription factor. It plays vital roles in the maintenance of embryonic stem cell properties, functions as an oncogene in leukemia, and has been recently proposed to use for cord blood expansion. The mechanism(s) by which SALL4 functions in normal human hematopoiesis, including identification of its target genes, still need to be explored.
Chromatin immunoprecipitation followed by microarray hybridization (ChIP-chip) was used for mapping SALL4 global gene targets in normal primary CD34+ cells. The results were then correlated with SALL4 functional studies in the CD34+ cells.
More than 1000 potential SALL4 downstream target genes have been identified, and validation of binding by ChIP-quantitative polymerase chain reaction was performed for 5% of potential targets. These include genes that are involving in hematopoietic differentiation and self-renewal, such as HOXA9, RUNX1, CD34, and PTEN. Down regulation of SALL4 expression using small-hairpin RNA in these cells led to decreased in vitro myeloid colony-forming abilities and impaired in vivo engraftment. Furthermore, HOXA9 was identified to be a major SALL4 target in normal human hematopoiesis and the loss of either SALL4 or HOXA9 expression in CD34+ cells shared a similar phenotype.
Taken together, SALL4 is a key regulator in normal human hematopoiesis and the mechanism of its function is at least in part through the HOXA9. Future study will determine whether modulating the SALL4/HOXA9 pathway can be used in cellular therapy such as cord blood expansion and/or myeloid engraftment.
干细胞因子 SALL4 是一种锌指转录因子。它在维持胚胎干细胞特性、作为白血病癌基因发挥作用方面发挥着重要作用，最近还被提议用于脐血扩增。SALL4 在正常人类造血中发挥作用的机制（包括鉴定其靶基因）仍需探索。
采用染色质免疫沉淀结合微阵列杂交（ChIP-chip）技术，对正常原代 CD34+细胞中 SALL4 的全基因组靶基因进行定位。然后将结果与 CD34+细胞中 SALL4 的功能研究相关联。
已经鉴定出超过 1000 个潜在的 SALL4 下游靶基因，并对 5%的潜在靶基因进行了 ChIP-定量聚合酶链反应的验证。这些基因包括参与造血分化和自我更新的基因，如 HOXA9、RUNX1、CD34 和 PTEN。在这些细胞中使用小发夹 RNA 下调 SALL4 表达，导致体外髓样集落形成能力降低和体内植入受损。此外，HOXA9 被鉴定为正常人类造血中 SALL4 的主要靶基因，CD34+细胞中 SALL4 或 HOXA9 表达的缺失具有相似的表型。
综上所述，SALL4 是正常人类造血中的关键调节因子，其功能机制至少部分通过 HOXA9。未来的研究将确定是否可以调节 SALL4/HOXA9 途径用于细胞治疗，如脐血扩增和/或髓样植入。
