Salman Huda, Shuai Xiao, Nguyen-Lefebvre Anh Thu, Giri Banabihari, Ren Mingqiang, Rauchman Michael, Robbins Lynn, Hou Wei, Korkaya Hasan, Ma Yupo
Georgia Regent University Cancer Center, Augusta, GA, USA.
Present address: Stony Brook University Cancer Center, Stony Brook, NY, USA.
Oncotarget. 2017 Dec 15;9(7):7442-7452. doi: 10.18632/oncotarget.23448. eCollection 2018 Jan 26.
Similar signaling pathways could operate in both normal hematopoietic stem and progenitor cells (HSPCs) and leukemia stem cells (LSCs). Thus, targeting LSCs signaling without substantial toxicities to normal HSPCs remains challenging. SALL1, is a member of the transcriptional network that regulates stem cell pluripotency, and lacks significant expression in most adult tissues, including normal bone marrow (NBM). We examined the expression and functional characterization of SALL1 in NBM and in acute myeloid leukemia (AML) using and assays. We showed that SALL1 is expressed preferentially in LSCs- enriched CD34+CD38- cell subpopulation but not in NBM. SALL1 inhibition resulted in decreased cellular proliferation and in inferior AML engraftment in NSG mice and it was also associated with upregulation of PTEN and downregulation of m-TOR, β-catenin, and NF-қB expression. These findings suggest that SALL1 inhibition interrupts leukemogenesis. Further studies to validate SALL1 as a potential biomarker for minimal residual disease (MRD) and to determine SALL1's role in prognostication are ongoing. Additionally, pre-clinical evaluation of SALL1 as a therapeutic target in AML is warranted.
相似的信号通路可能在正常造血干细胞和祖细胞（HSPCs）以及白血病干细胞（LSCs）中均发挥作用。因此，在不对正常HSPCs产生实质性毒性的情况下靶向LSCs信号传导仍然具有挑战性。SALL1是调节干细胞多能性的转录网络的成员，在包括正常骨髓（NBM）在内的大多数成年组织中缺乏显著表达。我们使用[具体实验方法1]和[具体实验方法2]检测了SALL1在NBM和急性髓系白血病（AML）中的表达及功能特性。我们发现SALL1优先表达于富含LSCs的CD34+CD38-细胞亚群，而在NBM中不表达。SALL1抑制导致细胞增殖减少，NSG小鼠体内AML植入能力下降，并且还与PTEN上调以及m-TOR、β-连环蛋白和NF-қB表达下调相关。这些发现表明SALL1抑制会中断白血病发生过程。正在进行进一步研究以验证SALL1作为微小残留病（MRD）潜在生物标志物的作用，并确定SALL1在预后中的作用。此外，有必要对SALL1作为AML治疗靶点进行临床前评估。
