title: Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells.
abstract: Human acute myeloid leukemia (AML) originates from rare leukemia stem cells (LSCs). Because these chemotherapy-resistant LSCs are thought to underlie disease relapse, effective therapeutic strategies specifically targeting these cells may be beneficial. Here, we report identification of a primary human LSC gene signature and functional characterization of human LSC-specific molecules in vivo in a mouse xenotransplantation model. In 32 of 61 (53%) patients with AML, either CD32 or CD25 or both were highly expressed in LSCs. CD32- or CD25-positive LSCs could initiate AML and were cell cycle-quiescent and chemotherapy-resistant in vivo. Normal human hematopoietic stem cells depleted of CD32- and CD25-positive cells maintained long-term multilineage hematopoietic reconstitution capacity in vivo, indicating the potential safety of treatments targeting these molecules. In addition to CD32 and CD25, quiescent LSCs within the bone marrow niche also expressed the transcription factor WT1 and the kinase HCK. These molecules are also promising targets for LSC-specific therapy.
authors.affiliation: Research Unit for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, 230-0045 Japan.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Saito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitamura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hijikata
authors.forename: Mariko
authors.initials: M
authors.lastname: Tomizawa-Murasawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Takagi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Uchida
authors.forename: Nahoko
authors.initials: N
authors.lastname: Suzuki
authors.forename: Akiko
authors.initials: A
authors.lastname: Sone
authors.forename: Yuho
authors.initials: Y
authors.lastname: Najima
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Ozawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Wake
authors.forename: Shuichi
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016026:Bone Marrow Transplantation / Q000379:methods; D002453:Cell Cycle; D019070:Cell Lineage; D002469:Cell Separation; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D007938:Leukemia / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D017452:Receptors, IgG / Q000096:biosynthesis; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D053645:Interleukin-2 Receptor alpha Subunit; D017452:Receptors, IgG