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

Yoshikane Kikushige; Toshihiro Miyamoto; Junichiro Yuda; Siamak Jabbarzadeh-Tabrizi; Takahiro Shima; Shin-ichiro Takayanagi; Hiroaki Niiro; Ayano Yurino; Kohta Miyawaki; Katsuto Takenaka; Hiromi Iwasaki; Koichi Akashi

doi:10.1016/j.stem.2015.07.011

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. Epub 2015 Aug 13.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Antibodies, Neoplasm / metabolism
Antigens, CD34 / metabolism
Autocrine Communication*
Blast Crisis / blood
Blast Crisis / pathology
Cell Line, Transformed
Cell Nucleus / metabolism
Cell Proliferation
Disease Progression*
Extracellular Signal-Regulated MAP Kinases / metabolism
Galectins / blood
Galectins / metabolism*
Hepatitis A Virus Cellular Receptor 2
Humans
Leukemia, Myeloid, Acute / blood
Leukemia, Myeloid, Acute / immunology
Leukemia, Myeloid, Acute / metabolism*
Leukemia, Myeloid, Acute / pathology*
Ligands
Membrane Proteins / metabolism*
Mice
Models, Biological
NF-kappa B / metabolism
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology*
Phosphorylation
Protein Binding
Protein Transport
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
Tumor Burden
Xenograft Model Antitumor Assays
beta Catenin / metabolism

Substances

Antibodies, Neoplasm
Antigens, CD34
Galectins
HAVCR2 protein, human
Hepatitis A Virus Cellular Receptor 2
LGALS9 protein, human
Ligands
Membrane Proteins
NF-kappa B
beta Catenin
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases