Molecular dissection of the leukemia-associated transcription factor, AML1/RUNX1,in hematopoietic regulation

急性髓系白血病1 （AML1，也称为runt相关转录因子1:RUNX1）编码一种转录因子，该转录因子在决定性造血的早期发展中起关键作用，是白血病相关基因畸变最常见的靶标。在本研究中，我们通过胚胎干细胞和全鼠水平的造血修复实验，研究了其在正常和白血病造血中的功能。我们的发现总结如下：1。AML1的转录抑制功能是通过其c端vwrpy基序介导的，在整个小鼠的早期造血发育中并不是必需的。基因修饰的小鼠系纯合携带敲入缺乏VWRPY-motif的AML1等位基因，表明基因保守的VWRPY-motif在胸腺早期发育和cd4表达中起重要作用。通过对170例白血病或相关疾病的筛查，我们发现5个（2.9%）新突变位于外显子3至6，对应于runt结构域。除1例沉默突变外，其余4例均为功能缺失型等位基因：其中2例为n端附近的移框突变，另外2例I150ins和K168为矮子结构域c端附近的插入突变，实验证明其无功能。这些数据进一步强调了AML1的单等位基因缺失是人类白血病发生的早期事件。

Acute Myeloid Leukemia 1 (AML1; also called as Runt-Related Transcription Factor 1: RUNX1) encodes a transcription factor which plays a pivotal role in early development of definitive hematopoiesis, and is the most frequent target of the leukemia-associated gene aberration. In this study, we examined its function along with normal and leukemic hematopoiesis by means of hematopoietic rescue assay at embryonic stem cell and entire mouse levels. What we found are summarized as follows:1.Transcription-repressive function of AML1,which is mediated through its C-terminal VWRPY-motif, is not essential for the early hematopoietic development in the context of the entire mouse.2.Genome-modified mouse lines which homozygously harbor knocked-in AML1 allele lacking of VWRPY-motif revealed that the genetically conserved VWRPY-motif plays an important role in early development of thymus and CD4-expression.3.By screening 170 cases of leukemia or related disorders, we found five (2.9%) novel mutations within the exons 3 through 6,which correspond to the runt domain. Apart from a case with a silent mutation, the remaining four cases were all loss-of-function type of the allele : Two of them were frame-shift near the N-terminus, and the other two, I150ins and K168,were insertion mutations near the C-terminal end of the runt domain which were experimentally proven to be non-functional. These data further underscore the notice that one-allele loss of AML1 serves as an early event of human leukemogenesis.