title: Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia.
abstract: Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.
authors.affiliation: Laboratory for Human Disease Models RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan;
authors.forename: Yuki
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Laboratory for Human Disease Models RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kuroki
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hijikata
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan;
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.affiliation: Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan;
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomizawa
authors.affiliation: Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan;
authors.forename: Mariko
authors.initials: M
authors.lastname: Eguchi
authors.affiliation: Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan;
authors.forename: Minenori
authors.initials: M
authors.lastname: Eguchi-Ishimae
authors.affiliation: Laboratory for Human Disease Models RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Akiko
authors.initials: A
authors.lastname: Kaneko
authors.affiliation: Laboratory for Human Disease Models RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Rintaro
authors.initials: R
authors.lastname: Ono
authors.affiliation: Laboratory for Human Disease Models RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato
authors.affiliation: Laboratory for Human Disease Models RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Nahoko
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Laboratory for Human Disease Models RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Saera
authors.initials: S
authors.lastname: Fujiki
authors.affiliation: Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan;
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Koh
authors.affiliation: Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan;
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ishii
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME; and.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Kazusa DNA Research Institute, Kisarazu, Chiba, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan;
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
authors.affiliation: Laboratory for Human Disease Models RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics*; D051927:CD24 Antigen / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D017452:Receptors, IgG / Q000235:genetics; D060245:Tetraspanin 29 / Q000235:genetics
chemical_list: D018952:Antigens, CD34; D051927:CD24 Antigen; C113855:MLL-AF4 fusion protein, human; C474558:MLL-AF9 fusion protein, human; C425207:MLL-ENL oncoprotein, human; D015514:Oncogene Proteins, Fusion; D017452:Receptors, IgG; D060245:Tetraspanin 29; D051788:Myeloid-Lymphoid Leukemia Protein