Kwok Colin, Zeisig Bernd B, Qiu Jihui, Dong Shuo, So Chi Wai Eric
Hemato-Oncology Section, The Institute of Cancer Research, Greater London SM2 5NG, UK.
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2853-8. doi: 10.1073/pnas.0810558106. Epub 2009 Feb 6.
Although both heterodimeric subunits of core binding factors (AML1/RUNX1 and CBFbeta) essential for normal hematopoiesis are frequently mutated to form different chimeric fusion proteins in acute leukemia, the underlying molecular mechanisms and structural domains required for cellular transformation remain largely unknown. Despite the critical role of CBFbeta for wild-type AML1 function and its direct involvement in chromosomal translocation, we demonstrate that both the expression and interaction with CBFbeta are superfluous for AML1-ETO (AE)-mediated transformation of primary hematopoietic cells. Similarly, the hetero-oligomeric interaction with transcriptional repressor ETO family proteins and the highly conserved NHR1 domain in AE fusion are also dispensable for transforming activity. In contrast, AE-mediated transformation is critically dependent on the DNA binding and homo-oligomeric properties of the fusion. Abolishment of homo-oligomerization by a small-molecule inhibitor could specifically suppress AML1 fusion-mediated transformation of primary hematopoietic cells. Together, these results not only identify the essential molecular components but also potential avenues for therapeutic targeting of AE-mediated leukemogenesis.
虽然核心结合因子（AML1/RUNX1和CBFβ）的两个异二聚体亚基对正常造血至关重要，但在急性白血病中它们经常发生突变，形成不同的嵌合融合蛋白，然而细胞转化所需的潜在分子机制和结构域仍 largely 未知。尽管CBFβ对野生型AML1功能起关键作用且直接参与染色体易位，但我们证明，对于AML1-ETO（AE）介导的原代造血细胞转化而言，CBFβ的表达及其与之的相互作用都是多余的。同样，与转录抑制因子ETO家族蛋白的异源寡聚体相互作用以及AE融合中高度保守的NHR1结构域对于转化活性也是可有可无的。相反，AE介导的转化严重依赖于融合蛋白的DNA结合和同源寡聚特性。小分子抑制剂消除同源寡聚化可特异性抑制AML1融合介导的原代造血细胞转化。总之，这些结果不仅确定了关键的分子成分，还为AE介导的白血病发生的治疗靶点提供了潜在途径。
