Yokoyama Takashi, Nakatake Mayuka, Kuwata Takeshi, Couzinet Arnaud, Goitsuka Ryo, Tsutsumi Shuichi, Aburatani Hiroyuki, Valk Peter J M, Delwel Ruud, Nakamura Takuro
J Clin Invest. 2016 May 2;126(5):1664-78. doi: 10.1172/JCI81516. Epub 2016 Mar 28.
The TALE-class homeoprotein MEIS1 specifically collaborates with HOXA9 to drive myeloid leukemogenesis. Although MEIS1 alone has only a moderate effect on cell proliferation in vitro, it is essential for the development of HOXA9-induced leukemia in vivo. Here, using murine models of leukemogenesis, we have shown that MEIS1 promotes leukemic cell homing and engraftment in bone marrow and enhances cell-cell interactions and cytokine-mediated cell migration. We analyzed global DNA binding of MEIS1 in leukemic cells as well as gene expression alterations in MEIS1-deficent cells and identified synaptotagmin-like 1 (Sytl1, also known as Slp1) as the MEIS1 target gene that cooperates with Hoxa9 in leukemogenesis. Replacement of SYTL1 in MEIS1-deficent cells restored both cell migration and engraftment. Further analysis revealed that SYTL1 promotes cell migration via activation of the CXCL12/CXCR4 axis, as SYTL1 determines intracellular trafficking of CXCR4. Together, our results reveal that MEIS1, through induction of SYTL1, promotes leukemogenesis and supports leukemic cell homing and engraftment, facilitating interactions between leukemic cells and bone marrow stroma.
TALE 类同源异型结构域蛋白 MEIS1 特别与 HOXA9 协同作用以驱动髓系白血病发生。虽然单独的 MEIS1 在体外对细胞增殖只有中等程度的影响，但它对 HOXA9 诱导的白血病在体内的发展至关重要。在此，利用白血病发生的小鼠模型，我们已表明 MEIS1 促进白血病细胞归巢并植入骨髓，并增强细胞间相互作用以及细胞因子介导的细胞迁移。我们分析了白血病细胞中 MEIS1 的全基因组 DNA 结合情况以及 MEIS1 缺陷细胞中的基因表达变化，并确定了与 Hoxa9 在白血病发生中协同作用的类似突触结合蛋白 1（Sytl1，也称为 Slp1）作为 MEIS1 的靶基因。在 MEIS1 缺陷细胞中替换 SYTL1 可恢复细胞迁移和植入。进一步分析表明，SYTL1 通过激活 CXCL12/CXCR4 轴促进细胞迁移，因为 SYTL1 决定了 CXCR4 的细胞内运输。总之，我们的结果表明，MEIS1 通过诱导 SYTL1 促进白血病发生，并支持白血病细胞归巢和植入，促进白血病细胞与骨髓基质之间的相互作用。
