title: The IL-2/CD25 axis maintains distinct subsets of chronic myeloid leukemia-initiating cells.
abstract: Just as normal stem cells require niche cells for survival, leukemia-initiating cells (LICs) may also require niche cells for their maintenance. Chronic myeloid leukemia (CML) is caused by the activity of BCR-ABL, a constitutively active tyrosine kinase. CML therapy with tyrosine kinase inhibitors is highly effective; however, due to the persistence of residual LICs, it is not curative. Several factors are known to support CML LICs, but purification of LICs and a thorough understanding of their niche signals have not yet been achieved. Using a CML-like mouse model of myeloproliferative disease, we demonstrate that CML LICs can be divided into CD25(+)FcεRIα(-) Lineage marker (Lin)(-) Sca-1(+)c-Kit(+) (F(-)LSK) cells and CD25(-)F(-)LSK cells. The CD25(+)F(-)LSK cells had multilineage differentiation capacity, with a preference toward cytokine-producing mast cell commitment. Although cells interconverted between CD25(-)F(-)LSK and CD25(+)F(-)LSK status, the CD25(+)F(-)LSK cells exhibited higher LIC capacity. Our findings suggest that interleukin-2 derived from the microenvironment and CD25 expressed on CML LICs constitute a novel signaling axis. The high levels of CD25 expression in the CD34(+)CD38(-) fraction of human CML cells indicate that CD25(+) LICs constitute an "LIC-derived niche" that could be preferentially targeted in therapy for CML.
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Chiharu I
authors.initials: CI
authors.lastname: Kobayashi
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakamura-Ishizu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kataoka
authors.forename: Keiki
authors.initials: K
authors.lastname: Kumano
authors.forename: Hideo
authors.initials: H
authors.lastname: Akiyama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Sudo
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D018418:Th2 Cells / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit