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Title:
Identification and characterization of cancer stem cells in a Tax-transgenic mouse model of adult T-cell leukemia/lymphoma

Takuo Mizukami, Ph.D
Department of Safety Research on Blood and Biological products,
National Institute of Infectious Diseases.

Abstract:
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.
Gene expression signature in the CSCs suggested 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.
In addition to ATL-CSCs, we will introduce malignant stem cells in MDS ( del [5q]) patient through the Lenalidomide treatment, recently published in NEJM.

References:
Yamazaki J, Mizukami T, Takizawa K, Kuramitsu M, Momose H, Masumi A, Ami Y, Hasegawa H, Hall WW, Tsujimoto H, Hamaguchi I, Yamaguchi K. Identification of cancer stem cells in a Tax-transgenic (Tax-Tg) mouse model of adult T-cell leukemia/lymphoma. Blood . 2009; 114(13): 2709-2720.

Tehranchi R, Woll PS, Anderson K, Buza-Vidas N, Mizukami T, Mead AJ, Astrand-Grundstrom I, Strombeck B, Horvat A, Ferry H, Dhanda RS, Hast R, Ryden T, Vyas P, Gohring G, Schlegelberger B, Johansson B, Hellstrom-Lindberg E, List A, Nilsson L, Jacobsen SE. Persistent malignant stem cells in del (5q) myelodysplasia in remission. N Engl J Med . 2010; 363 (11): 1025-1037.