Overexpression of RUNX3 Represses RUNX1 to Drive Transformation of Myelodysplastic Syndrome
Overexpression of RUNX3 Represses RUNX1 to Drive Transformation of Myelodysplastic Syndrome
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DOI：
10.1158/0008-5472.can-19-3167
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发表时间：
2020-06-15
期刊：
影响因子：
11.2
通讯作者：
Sashida, Goro
中科院分区：
文献类型：
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作者：
Yokomizo-Nakano, Takako;Kubota, Sho;Sashida, Goro
RUNX 3是一种RUNX家族转录因子，调节正常的造血，并在人类和小鼠的各种肿瘤中作为肿瘤抑制因子发挥作用。然而，新兴的研究已经记录了骨髓增生异常综合征（MDS）患者亚组的造血干/祖细胞（HSPC）中RUNX 3的表达增加，显示出更差的结果，表明RUNX 3在血液恶性肿瘤的发病机制中具有致癌功能。为了阐明RUNX 3在体内MDS发病机制中的致癌功能，我们建立了一种RUNX 3表达的Tet 2缺陷小鼠模型，该模型具有MDS患者的全血细胞减少和发育不良血细胞特征。表达RUNX 3的细胞显著抑制Runx 1的表达水平，Runx 1是正常和恶性细胞中造血的关键调节因子，以及其靶基因，其中包括关键的肿瘤抑制因子，如Cebpa和Csf 1 r。RUNX 3结合这些基因，并在Tet 2缺陷细胞中重塑其Runx 1结合区域。RUNX 3的过表达抑制Runx 1的转录功能并损害造血，从而在Tet 2不存在的情况下促进MDS的发展，表明RUNX 3是一种癌基因。此外，RUNX 3的过表达激活了Myc靶基因的转录，并使细胞对Myc-Max异源二聚化的抑制敏感。总的来说，这些结果揭示了机制，RUNX 3过表达发挥致癌作用的细胞功能和转录程序Tet 2缺陷的干细胞，以驱动MDS.Significance的转化：这项研究定义了致癌作用的转录因子RUNX 3在驱动骨髓增生异常综合征的转化，突出RUNX 3作为一个潜在的治疗干预目标。
RUNX3, a RUNX family transcription factor, regulates normal hematopoiesis and functions as a tumor suppressor in various tumors in humans and mice. However, emerging studies have documented increased expression of RUNX3 in hematopoietic stem/progenitor cells (HSPC) of a subset of patients with myelodysplastic syndrome (MDS) showing a worse outcome, suggesting an oncogenic function for RUNX3 in the pathogenesis of hematologic malignancies. To elucidate the oncogenic function of RUNX3 in the pathogenesis of MDS in vivo, we generated a RUNX3- expressing, Tet2-deficient mouse model with the pancytopenia and dysplastic blood cells characteristic of MDS in patients. RUNX3-expressing cells markedly suppressed the expression levels of Runx1, a critical regulator of hemaotpoiesis in normal and malignant cells, as well as its target genes, which included crucial tumor suppressors such as Cebpa and Csf1r. RUNX3 bound these genes and remodeled their Runx1-binding regions in Tet2-deficient cells. Overexpression of RUNX3 inhibited the transcriptional function of Runx1 and compromised hematopoiesis to facilitate the development of MDS in the absence of Tet2, indicating that RUNX3 is an oncogene. Furthermore, overexpression of RUNX3 activated the transcription of Myc target genes and rendered cells sensitive to inhibition of Myc-Max heterodimerization. Collectively, these results reveal the mechanism by which RUNX3 overexpression exerts oncogenic effects on the cellular function of and transcriptional program in Tet2-deficient stem cells to drive the transformation of MDS.Significance: This study defines the oncogenic effects of transcription factor RUNX3 in driving the transformation of myelodysplastic syndrome, highlighting RUNX3 as a potential target for therapeutic intervention.