Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Leukemia. 2011 Apr;25(4):655-62. doi: 10.1038/leu.2010.301. Epub 2011 Jan 25.
Cytokine signaling pathways are frequent targets of oncogenic mutations in acute myeloid leukemia (AML), promoting proliferation and survival. We have previously shown that the transcription factor PLAGL2 promotes proliferation and cooperates with the leukemia fusion protein Cbfβ-SMMHC in AML development. Here, we show that PLAGL2 upregulates expression of the thrombopoietin receptor Mpl, using two consensus sites in its proximal promoter. We also show that Mpl overexpression efficiently cooperates with Cbfβ-SMMHC in development of leukemia in mice. Finally, we demonstrate that PlagL2-expressing leukemic cells show hyper-activation of Jak2 and downstream STAT5, Akt and Erk1/2 pathways in response to Thpo ligand. These results show that PlagL2 expression activates expression of Mpl in hematopoietic progenitors, and that upregulation of wild-type Mpl provides an oncogenic signal in cooperation with CBFβ-SMMHC in mice.
细胞因子信号通路是急性髓系白血病（AML）中致癌突变的常见靶点，促进增殖和存活。我们之前已经表明，转录因子 PLAGL2 促进增殖，并与 AML 发育中的白血病融合蛋白 Cbfβ-SMMHC 合作。在这里，我们表明 PLAGL2 通过其近端启动子中的两个共识位点上调血小板生成素受体 Mpl 的表达。我们还表明，Mpl 的过表达可有效地与 Cbfβ-SMMHC 合作，在小鼠中发展白血病。最后，我们证明表达 PlagL2 的白血病细胞在响应 Thpo 配体时显示 Jak2 和下游 STAT5、Akt 和 Erk1/2 途径的过度激活。这些结果表明 PlagL2 表达在造血祖细胞中激活 Mpl 的表达，并且野生型 Mpl 的上调在与 CBFβ-SMMHC 在小鼠中的合作中提供致癌信号。
