Kamath M B, Houston I B, Janovski A J, Zhu X, Gowrisankar S, Jegga A G, DeKoter R P
Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, USA.
Leukemia. 2008 Jun;22(6):1214-25. doi: 10.1038/leu.2008.67. Epub 2008 Mar 20.
The Ets transcription factor PU.1, encoded by the gene Sfpi1, functions in a concentration-dependent manner to promote myeloid and B-cell development and has been implicated in myeloid and lymphoid leukemias. To determine the consequences of reducing PU.1 concentration during hematopoiesis, we analyzed mice with two distinct hypomorphic alleles of Sfpi1 that produce PU.1 at approximately 20% (BN) or approximately 2% (Blac) of wild-type levels. Myeloid development was impaired in these mice, but less severely than in Sfpi1 null mice. To identify the downstream target genes that respond to changes in PU.1 concentration, we analyzed ex vivo interleukin-3 dependent myeloid cell lines established from Sfpi1(BN/BN), Sfpi1(Blac/Blac) and Sfpi1(-/-) fetal liver cells. Unexpectedly, many T-cell and natural killer cell genes were expressed in Sfpi1(-/-) cells and repressed in a dose-dependent manner in Sfpi1(Blac/Blac) and Sfpi1(BN/BN) cells. This pattern of dose-dependent T/NK-cell gene repression also occurred in ex vivo interleukin-7 dependent progenitor B cell lines. These results suggest that PU.1 functions in a concentration-dependent manner to repress T-cell and natural killer cell fates while promoting myeloid and B-cell fates.
由基因Sfpi1编码的Ets转录因子PU.1以浓度依赖的方式发挥作用，促进髓系和B细胞发育，并与髓系和淋巴系白血病有关。为了确定造血过程中降低PU.1浓度的后果，我们分析了具有两个不同Sfpi1低表达等位基因的小鼠，这两个等位基因产生的PU.1水平约为野生型水平的20%（BN）或约2%（Blac）。这些小鼠的髓系发育受损，但程度不如Sfpi1基因敲除小鼠严重。为了鉴定对PU .1浓度变化作出反应的下游靶基因，我们分析了从Sfpi1(BN/BN)、Sfpi1(Blac/Blac)和Sfpi1(-/-)胎肝细胞建立的体外白细胞介素-3依赖髓系细胞系。出乎意料的是，许多T细胞和自然杀伤细胞基因在Sfpi1(-/-)细胞中表达，并在Sfpi1(Blac/Blac)和Sfpi1(BN/BN)细胞中以剂量依赖的方式被抑制。这种剂量依赖性的T/NK细胞基因抑制模式也发生在体外白细胞介素-7依赖祖B细胞系中。这些结果表明，PU.1以浓度依赖的方式发挥作用，抑制T细胞和自然杀伤细胞命运，同时促进髓系和B细胞命运。
