Division of Molecular Genetics, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan.
Nature. 2010 Feb 4;463(7281):676-80. doi: 10.1038/nature08734.
Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a(+/+) and Foxo3a(-/-) mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-beta is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-beta inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-beta inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-beta-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.
慢性髓性白血病（CML）是由一种明确的遗传异常引起的，该异常会产生 BCR-ABL，这是一种组成性激活的酪氨酸激酶。人们普遍认为，BCR-ABL 激活 Akt 信号通路，抑制叉头框 O 转录因子（FOXO），从而支持 CML 细胞的增殖或抑制其凋亡。尽管酪氨酸激酶抑制剂伊马替尼的使用是 CML 治疗的一个突破，但伊马替尼并不能耗尽导致 CML 复发的白血病起始细胞（LIC）。在这里，我们使用同基因移植系统和一种 CML 样骨髓增生性疾病小鼠模型，表明 Foxo3a 在维持 CML LIC 中具有重要作用。我们发现，Foxo3a 核定位和 Akt 磷酸化减少的细胞在 LIC 群体中富集。Foxo3a(+/+)和 Foxo3a(-/-)小鼠来源的 LIC 的连续移植表明，LIC 缺乏 Foxo3a 显著降低了引起疾病的能力。此外，我们发现 TGF-β是 LIC 中 Akt 激活的关键调节剂，并控制 Foxo3a 的定位。TGF-β 抑制、Foxo3a 缺失和伊马替尼治疗的联合应用导致体内 CML 的有效耗竭。此外，TGF-β 抑制剂处理人 CML LIC 会损害其体外集落形成能力。我们的研究结果表明 TGF-β-FOXO 通路在维持 LIC 中具有关键作用，并加强了我们对体内特异性维持 CML LIC 的机制的理解。
