Runx2 induces acute myeloid leukemia in cooperation with Cbfβ-SMMHC in mice
Runx2 induces acute myeloid leukemia in cooperation with Cbfβ-SMMHC in mice
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DOI：
10.1182/blood-2008-06-162248
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发表时间：
2009-04-02
期刊：
影响因子：
20.3
通讯作者：
Castilla, Lucio H.
中科院分区：
文献类型：
--
作者：
Kuo, Ya-Huei;Zaidi, Sayyed K.;Castilla, Lucio H.
核心结合因子(CBF)是发育和分化程序的主要调节因子，CBF的改变经常与急性白血病相关。CBF成员RUNX2在造血中的作用还知之甚少。遗传证据表明，Runx2的解除调控可能会导致表达融合癌基因Cbfb-MYH11的小鼠发生髓系白血病。在这项研究中，我们证明了Runx2的持续表达调节了CBF-β-平滑肌肌球蛋白重链(SMMHC)介导的髓系白血病的发生。Runx2在造血干细胞中高表达，在髓系分化过程中呈下降趋势。持续的Runx2表达阻碍了髓系祖细胞的分化能力，并抑制了CBF靶标CSF1R、MPO、Cebpd、细胞周期抑制因子CDKN1A以及髓系标志物CEBPA和GFI1的表达。此外，全长Runx2与CBFβ-SMMHC在移植试验中合作开发白血病。此外，我们还发现Runx2的核基质靶向信号和DNA结合的矮小同源结构域是其白血病活性所必需的。相反，Runx2半功能不全延迟了急性髓系白血病的发病并降低了发病率。综上所述，这些结果表明，Runx2在干细胞室表达，干扰分化并抑制髓系室的CBF靶点，并调节CBFβ-SMMHC在小鼠白血病中的促白血病功能。(血。2009；113：3323-3332)
The core-binding factor (CBF) is a master regulator of developmental and differentiation programs, and CBF alterations are frequently associated with acute leukemia. The role of the CBF member RUNX2 in hematopoiesis is poorly understood. Genetic evidence suggests that deregulation of Runx2 may cause myeloid leukemia in mice expressing the fusion oncogene Cbfb-MYH11. In this study, we show that sustained expression of Runx2 modulates Cbf beta-smooth muscle myosin heavy chain (SMMHC)-mediated myeloid leukemia development. Expression of Runx2 is high in the hematopoietic stem cell compartment and decreases during myeloid differentiation. Sustained Runx2 expression hinders myeloid progenitor differentiation capacity and represses expression of CBF targets Csf1R, Mpo, Cebpd, the cell cycle inhibitor Cdkn1a, and myeloid markers Cebpa and Gfi1. In addition, full-length Runx2 cooperates with Cbf beta-SMMHC in leukemia development in transplantation assays. Furthermore, we show that the nuclear matrix-targeting signal and DNA-binding runt-homology domain of Runx2 are essential for its leukemogenic activity. Conversely, Runx2 haplo-insufficiency delays the onset and reduces the incidence of acute myeloid leukemia. Together, these results indicate that Runx2 is expressed in the stem cell compartment, interferes with differentiation and represses CBF targets in the myeloid compartment, and modulates the leukemogenic function of Cbf beta-SMMHC in mouse leukemia. (Blood. 2009;113:3323-3332)