title: Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region.
abstract: Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells. 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)2r gamma(null) mice carrying a complete null mutation of the cytokine gamma c upon the SCID background. 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.
authors.affiliation: Research Unit for Human Disease Models, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho Tsurumi-ku, Yokohama 230-0045, Japan. f_ishika@rcai.riken.jp
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ishikawa
authors.forename: Shuro
authors.initials: S
authors.lastname: Yoshida
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Saito
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hijikata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Ryu
authors.initials: R
authors.lastname: Nakamura
authors.forename: Toru
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tomiyama
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Saito
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Fukata
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Bonnie
authors.initials: B
authors.lastname: Lyons
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Uchida
authors.forename: Shuichi
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Mine
authors.initials: M
authors.lastname: Harada
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
mesh_terms: D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow; D002455:Cell Division; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010006:Osteoblasts