Yamazaki Jumpei, Mizukami Takuo, Takizawa Kazuya, Kuramitsu Madoka, Momose Haruka, Masumi Atsuko, Ami Yasushi, Hasegawa Hideki, Hall William W, Tsujimoto Hajime, Hamaguchi Isao, Yamaguchi Kazunari
Department of Safety Research on Blood and Biologics, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan.
Blood. 2009 Sep 24;114(13):2709-20. doi: 10.1182/blood-2008-08-174425. Epub 2009 Jul 7.
Adult T-cell leukemia/lymphoma (ATL) is a malignant lymphoproliferative disorder caused by HTLV-I infection. In ATL, chemotherapeutic responses are generally poor, which has suggested the existence of chemotherapy-resistant cancer stem cells (CSCs). To identify CSC candidates in ATL, we have focused on a Tax transgenic mouse (Tax-Tg) model, which reproduces ATL-like disease both in Tax-Tg animals and also after transfer of Tax-Tg splenic lymphomatous cells (SLCs) to nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Using a limiting dilution transplantation, it was estimated that one CSC existed per 10(4) SLCs (0.01%). In agreement with this, we have successfully identified candidate CSCs in a side population (0.06%), which overlapped with a minor population of CD38(-)/CD71(-)/CD117(+) cells (0.03%). Whereas lymphoma did not develop after transplantation of 10(2) SLCs, 10(2) CSCs could consistently regenerate the original lymphoma. In addition, lymphoma and CSCs could also be demonstrated in the bone marrow and CD117(+) CSCs were observed in both osteoblastic and vascular niches. In the CSCs, Tax, Notch1, and Bmi1 expression was down-regulated, suggesting that the CSCs were derived from Pro-T cells or early hematopoietic progenitor cells. Taken together, our data demonstrate that CSCs certainly exist and have the potential to regenerate lymphoma in our mouse model.
成人T细胞白血病/淋巴瘤（ATL）是一种由人类嗜T淋巴细胞病毒I型（HTLV-I）感染引起的恶性淋巴增殖性疾病。在ATL中，化疗反应通常较差，这提示存在化疗耐药的癌症干细胞（CSC）。为了鉴定ATL中的CSC候选细胞，我们聚焦于Tax转基因小鼠（Tax-Tg）模型，该模型在Tax-Tg动物体内以及将Tax-Tg脾淋巴瘤细胞（SLC）转移至非肥胖糖尿病/重症联合免疫缺陷（NOD/SCID）小鼠后均可重现ATL样疾病。通过有限稀释移植法估计，每10⁴个SLC中存在1个CSC（0.01%）。与此一致的是，我们在侧群细胞（0.06%）中成功鉴定出候选CSC，其与一小部分CD³⁸⁻/CD⁷¹⁻/CD¹¹⁷⁺细胞（0.03%）重叠。虽然移植10²个SLC后未发生淋巴瘤，但10²个CSC可始终再生出原始淋巴瘤。此外，在骨髓中也可证实存在淋巴瘤和CSC，并且在成骨细胞龛和血管龛中均观察到CD¹¹⁷⁺ CSC。在CSC中，Tax、Notch1和Bmi1的表达下调，提示CSC来源于原T细胞或早期造血祖细胞。综上所述，我们的数据表明在我们的小鼠模型中CSC确实存在且具有再生淋巴瘤的潜力。
