title: CD34+CD38+CD19+ as well as CD34+CD38-CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL.
abstract: The presence of rare malignant stem cells supplying a hierarchy of malignant cells has recently been reported. In human acute myelogenous leukemia (AML), the leukemia stem cells (LSCs) have been phenotypically restricted within the CD34+CD38- fraction. To understand the origin of malignant cells in primary human B-precursor acute lymphocytic leukemia (B-ALL), we established a novel in vivo xenotransplantation model. Purified CD34+CD38+CD19+, CD34+CD38-CD19+ and CD34+CD38-CD19- bone marrow (BM) or peripheral blood (PB) cells from three pediatric B-ALL patients were intravenously injected into sublethally irradiated newborn NOD/SCID/IL2rgamma(null) mice. We found that both CD34+CD38+CD19+ and CD34+CD38-CD19+ cells initiate B-ALL in primary recipients, whereas the recipients of CD34+CD38-CD10-CD19- cells showed normal human hematopoietic repopulation. The extent of leukemic infiltration into the spleen, liver and kidney was similar between the recipients transplanted with CD34+CD38+CD19+ cells and those transplanted with CD34+CD38-CD19+ cells. In each of the three cases studied, transplantation of CD34+CD38+CD19+ cells resulted in the development of B-ALL in secondary recipients, demonstrating self-renewal capacity. The identification of CD34+CD38+CD19+ self-renewing B-ALL cells proposes a hierarchy of leukemia-initiating cells (LICs) distinct from that of AML. Recapitulation of patient B-ALL in NOD/SCID/IL2rgamma(null) recipients provides a powerful tool for directly studying leukemogenesis and for developing therapeutic strategies.
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kong
authors.forename: S
authors.initials: S
authors.lastname: Yoshida
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: T
authors.initials: T
authors.lastname: Doi
authors.forename: Y
authors.initials: Y
authors.lastname: Nagatoshi
authors.forename: M
authors.initials: M
authors.lastname: Fukata
authors.forename: N
authors.initials: N
authors.lastname: Saito
authors.forename: S M
authors.initials: SM
authors.lastname: Yang
authors.forename: C
authors.initials: C
authors.lastname: Iwamoto
authors.forename: J
authors.initials: J
authors.lastname: Okamura
authors.forename: K Y
authors.initials: KY
authors.lastname: Liu
authors.forename: X J
authors.initials: XJ
authors.lastname: Huang
authors.forename: D P
authors.initials: DP
authors.lastname: Lu
authors.forename: L D
authors.initials: LD
authors.lastname: Shultz
authors.forename: M
authors.initials: M
authors.lastname: Harada
authors.forename: F
authors.initials: F
authors.lastname: Ishikawa
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D018941:Antigens, CD19 / Q000378:metabolism*; D018952:Antigens, CD34 / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002648:Child; D005434:Flow Cytometry; D006085:Graft Survival; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014916:Whole-Body Irradiation
chemical_list: D018941:Antigens, CD19; D018952:Antigens, CD34; D051997:ADP-ribosyl Cyclase 1