Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes
Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes
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DOI：
10.1073/pnas.0810558106
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发表时间：
2009-02-24
影响因子：
11.1
通讯作者：
So, Chi Wai Eric
中科院分区：
文献类型：
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作者：
Kwok, Colin;Zeisig, Bernd B.;So, Chi Wai Eric
虽然两个异源二聚体亚基的核心结合因子（AML 1/RUNX 1和CBF β）必须正常造血细胞经常突变，形成不同的嵌合融合蛋白在急性白血病，潜在的分子机制和结构域所需的细胞转化仍然在很大程度上未知。尽管CBF β对野生型AML 1功能及其直接参与染色体易位具有关键作用，但我们证明了CBF β的表达和相互作用对于AML 1-ETO（AE）介导的原代造血细胞转化是多余的。类似地，与转录抑制因子ETO家族蛋白的异源寡聚相互作用和AE融合中高度保守的NHR 1结构域也被证实具有转化活性。相反，AE介导的转化关键取决于融合体的DNA结合和同源寡聚体性质。通过小分子抑制剂消除同源寡聚化可以特异性抑制AML 1融合介导的原代造血细胞转化。总之，这些结果不仅确定了必要的分子组分，而且还确定了AE介导的白血病发生的治疗靶向的潜在途径。
Although both heterodimeric subunits of core binding factors (AML1/RUNX1 and CBF beta) 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 CBF beta for wild-type AML1 function and its direct involvement in chromosomal translocation, we demonstrate that both the expression and interaction with CBF beta 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.