西亚试剂：Chemotherapy-resistant human AML stem cells home to and eng

Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region

Fumihiko Ishikawa1,3, Shuro Yoshida1,3, Yoriko Saito1,5, Atsushi Hijikata2, Hiroshi Kitamura2, Satoshi Tanaka6, Ryu Nakamura7, Toru Tanaka7, Hiroko Tomiyama6, Noriyuki Saito3, Mitsuhiro Fukata3, Toshihiro Miyamoto4, Bonnie Lyons8, Koichi Ohshima9, Naoyuki Uchida10, Shuichi Taniguchi10, Osamu Ohara2,11, Koichi Akashi4,12, Mine Harada3 & Leonard D Shultz8

Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells1, 2, 3. To understand the functional properties of human LS cells, we developed a primary human AML xenotransplantation model using newborn nonobese diabetic/severe combined immunodeficient/interleukin (NOD/SCID/IL)2rnull mice carrying a complete null mutation of the cytokine c upon the SCID background4. Using this model, we demonstrated that LS cells exclusively recapitulate AML and retain self-renewal capacity in vivo. They home to and engraft within the osteoblast-rich area of the bone marrow, where AML cells are protected from chemotherapy-induced apoptosis. Quiescence of human LS cells may be a mechanism underlying resistance to cell cycle–dependent cytotoxic therapy. Global transcriptional profiling identified LS cell–specific transcripts that are stable through serial transplantation. These results indicate the potential utility of this AML xenograft model in the development of novel therapeutic strategies targeted at LS cells.