Stat5 deficiency decreases transcriptional heterogeneity and supports emergence of hematopoietic sub-populations.
Stat5 deficiency decreases transcriptional heterogeneity and supports emergence of hematopoietic sub-populations.
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DOI：
10.18632/oncotarget.15236
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发表时间：
2017-04-04
期刊：
影响因子：
--
通讯作者：
Bunting KD
中科院分区：
文献类型：
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作者：
Wang Z;Bunting KD
衰老与造血功能的显着变化有关，包括克隆优势、贫血、骨髓恶性肿瘤以及信号转导器和转录激活剂 5 (Stat5) 激活的减少。在之前的研究中，Stat5 缺失令人惊讶地放大了 FLT3/ITD+ 骨髓扩张或 Myc 驱动的淋巴扩张。在这里，我们发现 Stat5 缺陷对单分选的 c-Kit+Lin−Sca-1+ (KLS) 细胞或 CD150+CD48−KLS 长期再生造血干细胞 (LT-HSC) 的转录异质性有很大影响。对选定的多谱系造血调节因子进行单细胞聚合酶链反应（PCR）。通过细胞周期调节和白血病相关基因表达的增加，鉴定出至少两个显性亚群。此外，在最高表达四分位数的细胞中，大多数基因比例过高。在野生型 KLS 细胞中，Stat5 mRNA 水平也与多个基因密切相关。由于异质性随着年龄、炎症或致癌应激而降低，这些结果提供了与 Stat5 表达的潜在机制联系。
Aging is associated with significant changes in hematopoiesis, including clonal dominance, anemia, myeloid malignancies, and reduced activation of signal transducer and activator of transcription 5 (Stat5). In previous studies, Stat5 deletion surprisingly amplified FLT3/ITD+ myeloid expansion or Myc-driven lymphoid expansion. Here we show that Stat5 deficiency has a strong impact upon transcriptional heterogeneity in single sorted c-Kit+Lin−Sca-1+ (KLS) cells or CD150+CD48− KLS long-term repopulating hematopoietic stem cells (LT-HSC). Single cell polymerase chain reaction (PCR) was performed on selected regulators of multi-lineage hematopoiesis. At least two dominant sub-populations were identified by increased expression of cell cycle regulatory and leukemia-associated genes. Furthermore, in the top expressing quartile of cells, the majority of genes were proportionally overrepresented. In wild-type KLS cells, Stat5 mRNA levels were also strongly correlated with several genes. Since heterogeneity decreases with age or inflammatory or oncogenic stress, these results provide a potential mechanistic linkage to Stat5 expression.