A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression.
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.
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.
Yoshikane
Y
Kikushige
Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
Toshihiro
T
Miyamoto
Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
Junichiro
J
Yuda
Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
Siamak
S
Jabbarzadeh-Tabrizi
Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
Takahiro
T
Shima
Oncology Research Laboratories, Oncology R&D Unit, R&D Division, Kyowa Hakko Kirin Company, Limited, Tokyo 194-8533, Japan.
Shin-ichiro
S
Takayanagi
Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
Hiroaki
H
Niiro
Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
Ayano
A
Yurino
Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
Kohta
K
Miyawaki
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan.
Katsuto
K
Takenaka
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan.
Hiromi
H
Iwasaki
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: akashi@med.kyushu-u.ac.jp.
Koichi
K
Akashi
D000328:Adult; D000818:Animals; D000912:Antibodies, Neoplasm / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D019898:Autocrine Communication; D001752:Blast Crisis / Q000097:blood / Q000473:pathology; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D037161:Galectins / Q000097:blood / Q000378:metabolism*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
D000912:Antibodies, Neoplasm; D018952:Antigens, CD34; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D008024:Ligands; D008565:Membrane Proteins; D016328:NF-kappa B; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases