Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cancer Cell. 2010 May 18;17(5):455-68. doi: 10.1016/j.ccr.2010.03.022.
Dominant RUNX1 inhibition has been proposed as a common pathway for CBF leukemia. CBF beta-SMMHC, a fusion protein in human acute myeloid leukemia (AML), dominantly inhibits RUNX1 largely through its RUNX1 high-affinity binding domain (HABD). However, the type I CBF beta-SMMHC fusion in AML patients lacks HABD. Here, we report that the type I CBF beta-SMMHC protein binds RUNX1 inefficiently. Knockin mice expressing CBF beta-SMMHC with a HABD deletion developed leukemia quickly, even though hematopoietic defects associated with Runx1-inhibition were partially rescued. A larger pool of leukemia-initiating cells, increased MN1 expression, and retention of RUNX1 phosphorylation are potential mechanisms for accelerated leukemia development in these mice. Our data suggest that RUNX1 dominant inhibition may not be a critical step for leukemogenesis by CBF beta-SMMHC.
显性 RUNX1 抑制被认为是 CBF 白血病的共同途径。CBF beta-SMMHC 是人类急性髓系白血病（AML）中的一种融合蛋白，通过其 RUNX1 高亲和力结合域（HABD）显著抑制 RUNX1。然而，AML 患者的 I 型 CBF beta-SMMHC 融合缺乏 HABD。在这里，我们报告 I 型 CBF beta-SMMHC 蛋白与 RUNX1 的结合效率低下。表达具有 HABD 缺失的 CBF beta-SMMHC 的基因敲入小鼠很快发展为白血病，尽管与 Runx1 抑制相关的造血缺陷得到部分挽救。更大的白血病起始细胞池、MN1 表达增加以及 RUNX1 磷酸化的保留可能是这些小鼠白血病发展加速的潜在机制。我们的数据表明，RUNX1 显性抑制可能不是 CBF beta-SMMHC 引起白血病发生的关键步骤。
