Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Innovative Technology Laboratories, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan; and.
Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;
Blood. 2014 Dec 4;124(24):3587-96. doi: 10.1182/blood-2013-12-546275. Epub 2014 Oct 8.
Ecotropic viral integration site 1 (Evi1) is a transcription factor that is highly expressed in hematopoietic stem cells and is crucial for their self-renewal capacity. Aberrant expression of Evi1 is observed in 5% to 10% of de novo acute myeloid leukemia (AML) patients and predicts poor prognosis, reflecting multiple leukemogenic properties of Evi1. Here, we show that thrombopoietin (THPO) signaling is implicated in growth and survival of Evi1-expressing cells using a mouse model of Evi1 leukemia. We first identified that the expression of megakaryocytic surface molecules such as ITGA2B (CD41) and the THPO receptor, MPL, positively correlates with EVI1 expression in AML patients. In agreement with this finding, a subpopulation of bone marrow and spleen cells derived from Evi1 leukemia mice expressed both CD41 and Mpl. CD41(+) Evi1 leukemia cells induced secondary leukemia more efficiently than CD41(-) cells in a serial bone marrow transplantation assay. Importantly, the CD41(+) cells predominantly expressing Mpl effectively proliferated and survived on OP9 stromal cells in the presence of THPO via upregulating BCL-xL expression, suggesting an essential role of the THPO/MPL/BCL-xL cascade in enhancing the progression of Evi1 leukemia. These observations provide a novel aspect of the diverse functions of Evi1 in leukemogenesis.
嗜骨髓病毒整合位点 1（Evi1）是一种转录因子，在造血干细胞中高度表达，对其自我更新能力至关重要。在 5%至 10%的新发急性髓系白血病（AML）患者中观察到 Evi1 的异常表达，这预示着预后不良，反映了 Evi1 的多种白血病发生特性。在这里，我们使用 Evi1 白血病的小鼠模型表明，血小板生成素（THPO）信号参与了表达 Evi1 的细胞的生长和存活。我们首先确定了巨核细胞表面分子如 ITGA2B（CD41）和 THPO 受体 MPL 的表达与 AML 患者中 EVI1 的表达呈正相关。与这一发现一致的是，Evi1 白血病小鼠的骨髓和脾脏细胞的一个亚群表达 CD41 和 Mpl。在连续骨髓移植实验中，CD41(+)Evi1 白血病细胞比 CD41(-)细胞更有效地诱导继发性白血病。重要的是，CD41(+)细胞主要表达 Mpl，在 THPO 的存在下通过上调 BCL-xL 表达有效地增殖和存活于 OP9 基质细胞上，这表明 THPO/MPL/BCL-xL 级联在增强 Evi1 白血病进展中起重要作用。这些观察结果为 Evi1 在白血病发生中的多种功能提供了一个新的方面。
