Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Blood. 2011 Mar 24;117(12):3320-30. doi: 10.1182/blood-2010-08-303669. Epub 2011 Jan 24.
The transcription factor signal transducer and activator of transcription 5 (STAT5) fulfills essential roles in self-renewal in mouse and human hematopoietic stem cells (HSCs), and its persistent activation contributes to leukemic transformation, although little molecular insight into the underlying mechanisms has been obtained. In the present study, we show that STAT5 can impose long-term expansion exclusively on human HSCs, not on progenitors. This was associated with an enhanced cobblestone formation under bone marrow stromal cells of STAT5-transduced HSCs. Hypoxia-induced factor 2α (HIF2α) was identified as a STAT5 target gene in HSCs, and chromatin immunoprecipitation studies revealed STAT5 binding to a site 344 base pairs upstream of the start codon of HIF2α. Lentiviral RNA interference (RNAi)-mediated down-modulation of HIF2α impaired STAT5-induced long-term expansion and HSC frequencies, whereas differentiation was not affected. Glucose uptake was elevated in STAT5-activated HSCs, and several genes associated with glucose metabolism were up-regulated by STAT5 in an HIF2α-dependent manner. Our studies indicate that pathways normally activated under hypoxia might be used by STAT5 under higher oxygen conditions to maintain and/or impose HSC self-renewal properties.
转录因子信号转导子和转录激活子 5（STAT5）在小鼠和人类造血干细胞（HSCs）的自我更新中发挥着重要作用，其持续激活有助于白血病的转化，尽管对于潜在的机制还没有得到多少分子上的了解。在本研究中，我们表明 STAT5 可以仅对人类 HSCs 进行长期扩增，而不是对祖细胞进行扩增。这与 STAT5 转导的 HSCs 在骨髓基质细胞下形成增强的鹅卵石形成有关。缺氧诱导因子 2α（HIF2α）被鉴定为 HSCs 中的 STAT5 靶基因，染色质免疫沉淀研究显示 STAT5 结合到 HIF2α起始密码子上游 344 个碱基对的位点。慢病毒 RNA 干扰（RNAi）介导的 HIF2α 下调削弱了 STAT5 诱导的长期扩增和 HSC 频率，而分化不受影响。STAT5 激活的 HSCs 中葡萄糖摄取增加，并且 STAT5 以 HIF2α依赖性方式上调与葡萄糖代谢相关的几个基因。我们的研究表明，在缺氧下正常激活的途径可能被 STAT5 在较高氧条件下用于维持和/或施加 HSC 自我更新特性。
