FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice.
FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice.
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DOI：
10.1038/leu.2015.161
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发表时间：
2016-01
期刊：
影响因子：
11.4
通讯作者：
Kousteni S
中科院分区：
文献类型：
--
作者：
Kode A;Mosialou I;Manavalan SJ;Rathinam CV;Friedman RA;Teruya-Feldstein J;Bhagat G;Berman E;Kousteni S
成骨细胞（骨形成细胞）影响造血干细胞（HSC）的自我更新和扩张，以及健康造血细胞和肿瘤细胞归巢到骨髓中。成骨细胞中β-连环蛋白的组成型激活足以改变骨髓和淋巴祖细胞的分化潜力，并引发小鼠急性髓系白血病（AML）的发展。我们在此表明，Notch1 是介导 HSC 中成骨细胞激活的 β-连环蛋白致白血病特性的受体。此外，使用细胞特异性基因失活小鼠模型，我们表明成骨细胞中的 FoxO1 表达是 β-连环蛋白的致白血病特性所必需的，并介导其致白血病特性。在分子水平上，FoxO1 与成骨细胞中的 β-连环蛋白相互作用，诱导 Notch 配体 Jagged-1 的表达。随后在长期再生的 HSC 祖细胞中激活 Notch 信号传导会诱导 HSC 发生白血病转化，并最终导致 AML 的发生。这些发现确定成骨细胞中表达的 FoxO1 是影响造血的一个因素，并提供了 FoxO1/激活的 β-连环蛋白相互作用导致 AML 的分子机制。这些观察结果支持了骨髓生态位是白血病诱发因素的观点，并提出了 FoxO1 致癌特性可能出现在其他组织中的可能性。
Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of β-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast-activated β-catenin in HSCs. Moreover, using cell-specific gene inactivation mouse models, we show that FoxO1 expression in osteoblasts is required for and mediates the leukemogenic properties of β-catenin. At the molecular level, FoxO1 interacts with β-catenin in osteoblasts to induce expression of the Notch ligand, Jagged-1. Subsequent activation of Notch signaling in long-term repopulating HSC progenitors induces the leukemogenic transformation of HSCs and ultimately leads to the development of AML. These findings identify FoxO1 expressed in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/activated β-catenin interaction results in AML. These observations support the notion that the bone marrow niche is an instigator of leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues.