Leukemogenic activity of Trib1

我们前期的研究表明Trib 1是一个白血病基因，也是Hoxa 9/Meis 1在髓系白血病发生中的协同者。我们已经确定Trib 1与MEK 1的相互作用以及随后由MEK 1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，我们还阐明了Trib 1激活MAP激酶途径也是C/EBPα降解所必需的。这些研究揭示了Trib 1作为连接RAS-MAPK通路与C/EBP转录因子的重要接头的作用，以及其在血液恶性肿瘤中的重要性。此外，我们已经确定了TRIB 1的体细胞点突变在人类唐氏综合征相关的急性巨核细胞白血病（DS-AMKL）的情况下。点突变导致假激酶结构域中精氨酸107氨基酸转化为亮氨酸。TRIB 1 R107 L突变在GATA 1突变消失时仍存在于缓解期白细胞中，表明TRIB 1突变是一个非常早期的遗传事件。将Trib 1 R107 L突变体导入小鼠骨髓细胞诱导AML，其潜伏期比野生型短。R107 L的表达使Trib 1对ERK 1/2磷酸化和C/EBPα降解的促进作用更为显著。这些结果表明TRIB 1 R107 L是DS-AMKL病例中的功能获得性突变。

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.