Cheng Chi Keung, Li Libby, Cheng Suk Hang, Lau Kin Mang, Chan Natalie P H, Wong Raymond S M, Shing Matthew M K, Li Chi Kong, Ng Margaret H L
Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
Blood. 2008 Oct 15;112(8):3391-402. doi: 10.1182/blood-2008-02-137083. Epub 2008 Jul 28.
RUNX3/AML2 is a Runt domain transcription factor like RUNX1/AML1 and RUNX2/AML3. Regulated by 2 promoters P1 and P2, RUNX3 is frequently inactivated by P2 methylation in solid tumors. Growing evidence has suggested a role of this transcription factor in hematopoiesis. However, genetic alterations have not been reported in blood cancers. In this study on 73 acute myeloid leukemia (AML) patients (44 children and 29 adults), we first showed that high RUNX3 expression among childhood AML was associated with a shortened event-free survival, and RUNX3 was significantly underexpressed in the prognostically favorable subgroup of AML with the t(8;21) and inv(16) translocations. We further demonstrated that this RUNX3 repression was mediated not by P2 methylation, but RUNX1-ETO and CBFbeta-MYH11, the fusion products of t(8;21) and inv(16), via a novel transcriptional mechanism that acts directly or indirectly in collaboration with RUNX1, on 2 conserved RUNX binding sites in the P1 promoter. In in vitro studies, ectopically expressed RUNX1-ETO and CBFbeta-MYH11 also inhibited endogenous RUNX3 expression. Taken together, RUNX3 was the first transcriptional target found to be commonly repressed by the t(8;21) and inv(16) fusion proteins and might have an important role in core-binding factor AML.
RUNX3/AML2是一种类似于RUNX1/AML1和RUNX2/AML3的Runt结构域转录因子。RUNX3受两个启动子P1和P2调控，在实体瘤中常因P2甲基化而失活。越来越多的证据表明该转录因子在造血过程中发挥作用。然而，血液系统恶性肿瘤中尚未报道有基因改变。在这项针对73例急性髓系白血病（AML）患者（44例儿童和29例成人）的研究中，我们首先发现儿童AML中RUNX3高表达与无事件生存期缩短相关，并且在具有t(8;21)和inv(16)易位的AML预后良好亚组中RUNX3明显低表达。我们进一步证明，这种RUNX3的抑制不是由P2甲基化介导的，而是由t(8;21)和inv(16)的融合产物RUNX1-ETO和CBFβ-MYH11通过一种新的转录机制介导的，该机制直接或间接与RUNX1协同作用于P1启动子中的2个保守RUNX结合位点。在体外研究中，异位表达的RUNX1-ETO和CBFβ-MYH11也抑制内源性RUNX3表达。综上所述，RUNX3是第一个被发现受t(8;21)和inv(16)融合蛋白共同抑制的转录靶点，可能在核心结合因子AML中起重要作用。
