Kikushige Yoshikane, Miyamoto Toshihiro
Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
Japan Society for the Promotion of Science, Tokyo, Japan.
Int J Hematol. 2015 Nov;102(5):528-35. doi: 10.1007/s12185-015-1740-1. Epub 2015 Feb 3.
Human malignancies progress through a multistep process that includes the development of critical somatic mutations over the clinical course. Recent novel findings have indicated that hematopoietic stem cells (HSCs), which have the potential to self-renew and differentiate into multilineage hematopoietic cells, are an important cellular target for the accumulation of critical somatic mutations in hematological malignancies and play a central role in myeloid malignancy development. In contrast to myeloid malignancies, mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), are thought to originate directly from differentiated mature lymphocytes; however, recent compelling data have shown that primitive HSCs and hematopoietic progenitor cells contribute to the pathogenesis of mature lymphoid malignancies. Several representative mutations of hematological malignancies have been identified within the HSCs of CLL and lymphoma patients, indicating that the self-renewing long-lived fraction of HSCs can serve as a reservoir for the development of oncogenic events. Novel mice models have been established as human mature lymphoma models, in which specific oncogenic events target the HSCs and immature progenitor cells. These data collectively suggest that HSCs can be the cellular target involved in the accumulation of oncogenic events in the pathogenesis of mature lymphoid and myeloid malignancies.
人类恶性肿瘤通过一个多步骤过程进展，该过程包括在临床病程中关键体细胞突变的发生。最近的新发现表明，具有自我更新和分化为多谱系造血细胞潜能的造血干细胞（HSC），是血液系统恶性肿瘤中关键体细胞突变积累的重要细胞靶点，并且在髓系恶性肿瘤发展中起核心作用。与髓系恶性肿瘤不同，成熟淋巴细胞恶性肿瘤，如慢性淋巴细胞白血病（CLL），被认为直接起源于分化成熟的淋巴细胞；然而，最近令人信服的数据表明，原始造血干细胞和造血祖细胞参与了成熟淋巴细胞恶性肿瘤的发病机制。在CLL和淋巴瘤患者的造血干细胞中已鉴定出几种血液系统恶性肿瘤的代表性突变，这表明造血干细胞中具有自我更新能力的长寿亚群可作为致癌事件发生发展的储存库。已建立了新型小鼠模型作为人类成熟淋巴瘤模型，其中特定致癌事件靶向造血干细胞和未成熟祖细胞。这些数据共同表明，造血干细胞可能是成熟淋巴细胞和髓系恶性肿瘤发病机制中致癌事件积累所涉及的细胞靶点。
