Kwon Hyog Young, Bajaj Jeevisha, Ito Takahiro, Blevins Allen, Konuma Takaaki, Weeks Joi, Lytle Nikki K, Koechlein Claire S, Rizzieri David, Chuah Charles, Oehler Vivian G, Sasik Roman, Hardiman Gary, Reya Tannishtha
Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Asan-si, Chungcheongnamdo 336-745, South Korea.
Cell Stem Cell. 2015 Aug 6;17(2):152-164. doi: 10.1016/j.stem.2015.06.006. Epub 2015 Jul 23.
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 Tetraspanin 3 is a target of the RNA binding protein Musashi 2, which plays a key role in AML. We generated Tspan3 knockout mice that 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.
急性髓系白血病（AML）是一种侵袭性癌症，可发生于成人和儿童，且常常对治疗产生耐药性。因此，识别AML增殖所需的信号是开发治疗该疾病新方法的关键一步。在此，我们表明四跨膜蛋白3（Tetraspanin 3）是RNA结合蛋白Musashi 2的一个靶点，而Musashi 2在AML中起关键作用。我们培育出了无明显缺陷的Tspan3基因敲除小鼠。然而，Tspan3缺失损害了白血病干细胞的自我更新和疾病传播，并显著提高了AML小鼠模型的存活率。此外，Tspan3抑制作用阻断了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，我们表明Tspan3缺乏会使对CXCL12/SDF-1的反应失效，并导致AML在生态位内定位缺陷。这些结果确定Tspan3是侵袭性白血病的重要调节因子，并突出了Tspan3在肿瘤发生中的作用。
