Tetraspanin 3 Is Required for the Development and Propagation of Acute Myelogenous Leukemia.
Tetraspanin 3 Is Required for the Development and Propagation of Acute Myelogenous Leukemia.
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DOI：
10.1016/j.stem.2015.06.006
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发表时间：
2015-08-06
期刊：
影响因子：
23.9
通讯作者：
Reya T
中科院分区：
文献类型：
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作者：
Kwon HY;Bajaj J;Ito T;Blevins A;Konuma T;Weeks J;Lytle NK;Koechlein CS;Rizzieri D;Chuah C;Oehler VG;Sasik R;Hardiman G;Reya T
急性髓性白血病（AML）是一种侵袭性癌症，可侵袭成人和儿童，并且经常对治疗产生耐药性。因此，识别AML传播所需的信号是开发治疗这种疾病的新方法的关键一步。本研究表明，Tetraspanin3是RNA结合蛋白Musashi2的靶标，而Musashi2在AML中起着关键作用。我们产生的Tspan3基因敲除小鼠出生时没有明显的缺陷。然而，Tspan3缺失会损害白血病干细胞的自我更新和疾病繁殖，并显著提高AML小鼠模型的存活率。此外，Tspan3抑制抑制了AML患者样本的生长，这表明Tspan3在人类疾病中也很重要。作为机制的一部分，我们发现tspan3缺陷使对CXCL12/SDF-1的应答失效，并导致AML定位在生态位内的缺陷。这些研究表明，Tspan3是侵袭性白血病的重要调节因子，并强调了Tspan3在肿瘤发生中的作用。
Acute Myelogenous Leukemia (AML) is an aggressive cancer that strikes both adults and children, and is frequently resistant to therapy. Thus, identifying signals needed for AML propagation is a critical step toward developing new approaches for treating this disease. Here we show that Tetraspanin3 is a target of the RNA binding protein Musashi2, which plays a key role in AML. We generated Tspan3 knockout mice which were born without overt defects. However, Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation, and markedly improved survival in mouse models of AML. Additionally, Tspan3 inhibition blocked growth of AML patient samples suggesting that Tspan3 is also important in human disease. As part of the mechanism, we show that Tspan3-deficiency disabled responses to CXCL12/SDF-1, and led to defects in AML localization within the niche. These identify Tspan3 as an important regulator of aggressive leukemias and highlight a role for Tspan3 in oncogenesis.