A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression

  • Cell Stem Cell. 2015 Sep 3;17(3):341-52. doi: 10.1016/j.stem.2015.07.011.
Yoshikane Kikushige  1 ,  Toshihiro Miyamoto  2 ,  Junichiro Yuda  2 ,  Siamak Jabbarzadeh-Tabrizi  2 ,  Takahiro Shima  2 ,  Shin-ichiro Takayanagi  3 ,  Hiroaki Niiro  2 ,  Ayano Yurino  2 ,  Kohta Miyawaki  2 ,  Katsuto Takenaka  4 ,  Hiromi Iwasaki  4 ,  Koichi Akashi  5
Affiliations
  • 1. Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan; Japan Society for the Promotion of Science (JSPS), Tokyo 102-0083, Japan.
  • 2. Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
  • 3. Oncology Research Laboratories, Oncology R&D Unit, R&D Division, Kyowa Hakko Kirin Company, Limited, Tokyo 194-8533, Japan.
  • 4. Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan.
  • 5. Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan. Electronic address: [email protected].
PMID: 26279267 DOI: 10.1016/j.stem.2015.07.011
Abstract

Signaling mechanisms underlying self-renewal of leukemic stem cells (LSCs) are poorly understood, and identifying pathways specifically active in LSCs could provide opportunities for therapeutic intervention. T-cell immunoglobin mucin-3 (TIM-3) is expressed on the surface of LSCs in many types of human acute myeloid leukemia (AML), but not on hematopoietic stem cells (HSCs). Here, we show that TIM-3 and its ligand, Galectin-9 (Gal-9), constitute an autocrine loop critical for LSC self-renewal and development of human AML. Serum Gal-9 levels were significantly elevated in AML patients and in mice xenografted with primary human AML samples, and neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML. Gal-9-mediated stimulation of TIM-3 co-activated NF-κB and β-catenin signaling, pathways known to promote LSC self-renewal. These changes were further associated with leukemic transformation of a variety of pre-leukemic disorders and together highlight that targeting the TIM-3/Gal-9 autocrine loop could be a useful strategy for treating myeloid leukemias.

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