Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia.
Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia.
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DOI：
10.1016/j.ccell.2017.03.001
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发表时间：
2017-04-10
期刊：
影响因子：
50.3
通讯作者：
Oellerich T
中科院分区：
文献类型：
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作者：
Mohr S;Doebele C;Comoglio F;Berg T;Beck J;Bohnenberger H;Alexe G;Corso J;Ströbel P;Wachter A;Beissbarth T;Schnütgen F;Cremer A;Haetscher N;Göllner S;Rouhi A;Palmqvist L;Rieger MA;Schroeder T;Bönig H;Müller-Tidow C;Kuchenbauer F;Schütz E;Green AR;Urlaub H;Stegmaier K;Humphries RK;Serve H;Oellerich T
转录因子Meis 1在Hox基因过表达的背景下驱动髓性白血病发生，但目前被认为是不可治疗的。因此，我们研究了由Hoxa 9和Meis 1转化的髓系祖细胞是否对靶向信号通路成瘾。一个全面的（磷酸）蛋白质组学分析表明，Meis 1增加Syk蛋白的表达和活性。Syk上调通过Meis 1依赖性反馈环发生。通过解剖这个环，我们发现Syk是miR-146 a的直接靶点，其表达通过转录因子PU.1由Meis 1间接调控。在Hoxa 9过表达的背景下，Syk信号转导诱导Meis 1，重现了Hoxa 9/Meis 1驱动的白血病的几个致白血病特征。最后，Syk抑制破坏了已确定的调节环，延长了Hoxa 9/Meis 1驱动的白血病小鼠的生存期。Meis 1调节Hoxa 9驱动的白血病中Syk的表达和激活Hoxa 9/Meis 1驱动的白血病中Syk的上调由miR-146 a介导Syk活性增加诱导Meis 1转录程序体内，Meis 1使Hoxa 9驱动的白血病对Syk抑制敏感Mohr et al.鉴定涉及PU.1、miR-146 a和Syk的Meis 1依赖性调节环，导致Hoxa 9/Meis 1转化的骨髓祖细胞对Syk活性成瘾。Syk抑制破坏了Hoxa 9/Meis 1驱动的急性髓性白血病小鼠的调节环和细胞存活
The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia. Meis1 regulates expression and activation of Syk in Hoxa9-driven leukemia Syk upregulation in Hoxa9/Meis1-driven leukemia is mediated by miR-146a Increased Syk activity induces a Meis1 transcriptional program In vivo, Meis1 sensitizes Hoxa9-driven leukemia to Syk inhibition Mohr et al. identify a Meis1-dependent regulatory loop involving PU.1, miR-146a, and Syk, resulting in the addiction to Syk activity in Hoxa9/Meis1-transformed myeloid progenitor cells. Syk inhibition disrupts the regulatory loop and prolongs survival of mice with Hoxa9/Meis1-driven acute myeloid leukemia.