Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors
Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors
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DOI：
10.1371/journal.pgen.1003713
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发表时间：
2013-09-01
期刊：
影响因子：
4.5
通讯作者：
Grimes, H. Leighton
中科院分区：
文献类型：
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作者：
Phelan, James D.;Saba, Ingrid;Grimes, H. Leighton
生长因子非依赖性1（Growth factor independent 1，Gfi 1）是一种转录抑制因子，最初被鉴定为在由Moloney鼠白血病病毒感染诱导的T细胞白血病中被激活的基因。Notch 1是一种跨膜受体，在人类T细胞急性淋巴细胞白血病（T-ALL）中经常发生突变。Gfi 1是淋巴性白血病发生和维持的重要因子，其缺乏显著阻碍了动物模型中Notch依赖性T-ALL的发生。在这里，我们表明，不成熟的造血细胞需要Gfi 1完全整合Notch激活的信号。Notch 1激活加上Gfi 1缺陷早期在T-谱系规范导致T细胞的戏剧性损失，而在后期阶段激活离开发展不受影响。在Gfi 1缺陷的多能前体中，Notch激活诱导致死性并且是细胞自主的。此外，没有Gfi 1，多能祖细胞不维持Notch 1激活的T-谱系前体典型的全局表达谱。与此一致，我们发现淋巴致敏多能祖细胞（LMPP）和早期T谱系祖细胞（ETP）在Gfi 1（-/-）小鼠中不能正常形成或发挥功能。这些缺陷与Gfi 1（-/-）祖细胞无法激活淋巴基因相关，包括IL 7 R、Rag 1、Flt 3和Notch 1。我们的数据表明，Gfi 1是造血前体所需的，以承受Notch 1激活和维持Notch 1依赖的转录编程，以确定早期T淋巴细胞系的身份。
Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a gene activated in T-cell leukemias induced by Moloney-murine-leukemia virus infection. Notch1 is a transmembrane receptor that is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL). Gfi1 is an important factor in the initiation and maintenance of lymphoid leukemias and its deficiency significantly impedes Notch dependent initiation of T-ALL in animal models. Here, we show that immature hematopoietic cells require Gfi1 to competently integrate Notch-activated signaling. Notch1 activation coupled with Gfi1 deficiency early in T-lineage specification leads to a dramatic loss of T-cells, whereas activation in later stages leaves development unaffected. In Gfi1 deficient multipotent precursors, Notch activation induces lethality and is cell autonomous. Further, without Gfi1, multipotent progenitors do not maintain Notch1-activated global expression profiles typical for T-lineage precursors. In agreement with this, we find that both lymphoid-primed multipotent progenitors (LMPP) and early T lineage progenitors (ETP) do not properly form or function in Gfi1(-/-) mice. These defects correlate with an inability of Gfi1(-/-) progenitors to activate lymphoid genes, including IL7R, Rag1, Flt3 and Notch1. Our data indicate that Gfi1 is required for hematopoietic precursors to withstand Notch1 activation and to maintain Notch1 dependent transcriptional programming to determine early T-lymphoid lineage identity.