Leukemogenic activity of Trib1

我们之前的研究表明Trib1是白血病疾病基因，也是Hoxa9/Meis1在髓性白血病发生中的合作者。我们已经发现Trib1与MEK1的相互作用以及随后由MEK1结合基序ILLHPWF介导的MAPK活性增强是白血病发生的关键分子机制。此外，我们已经阐明了Trib1激活MAP激酶途径也是C/EBPα降解所必需的。这些研究揭示了Trib1作为连接RAS-MAPK通路和C/EBP转录因子的重要接头的作用，以及它在血液恶性肿瘤中的重要性。此外，我们在一例唐氏综合征相关急性巨核母细胞白血病（DS-AMKL）患者中发现了TRIB1的体细胞点突变。点突变导致假激酶区域的氨基酸将精氨酸107转化为亮氨酸。当GATA1突变消失时，TRIB1 R107L突变仍然存在于缓解期的白细胞中，表明TRIB1突变是一个非常早期的遗传事件。将Trib1 R107L突变体引入小鼠骨髓细胞诱导急性髓性白血病的潜伏期比野生型短。此外，trb1对ERK1/2磷酸化和C/EBPα降解的增强作用在R107L表达时更为显著。这些结果表明，TRIB1 R107L在DS-AMKL病例中是一个功能获得突变。

Our previous study indicated that Trib1 is a leukemia disease gene as well as a collaborator of Hoxa9/Meis1 in myeloid leukemogenesis. We have identified that Trib1 interaction with MEK1 and subsequent enhanced MAPK activity that are mediated with the MEK1 binding motif, ILLHPWF, are key molecular mechanisms for leukemogenesis. In addition, we have clarified that activation of the MAP kinase pathway by Trib1 is also required for degradation of C/EBPα. These studies uncover the role of Trib1 as an important adaptor that connects the RAS-MAPK pathway with C/EBP transcription factors as well as its importance in hematological malignancies. Moreover, we have identified a somatic point mutation of TRIB1 in a human case of Down syndrome-related acute megakaryoblastic leukemia (DS-AMKL). The point mutation results in amino acid conversion arginine 107 to leucine in the pseudokinase domain. The TRIB1 R107L mutation remained in leukocytes of the remission stage when the GATA1 mutation disappeared, indicating that the TRIB1 mutation is a very early genetic event. Introduction of the Trib1 R107L mutant into murine bone marrow cells induced AML with shorter latency than that of wild type. Further, the enhancing effects of Trib1 on phosphorylation of ERK1/2 and degradation of C/EBPα were more remarkable by R107L expression. These results suggest that TRIB1 R107L is a gain-of-function mutation in a DS-AMKL case.