TY - JOUR
T1 - A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression
AU - Kikushige, Yoshikane
AU - Miyamoto, Toshihiro
AU - Yuda, Junichiro
AU - Jabbarzadeh-Tabrizi, Siamak
AU - Shima, Takahiro
AU - Takayanagi, Shin Ichiro
AU - Niiro, Hiroaki
AU - Yurino, Ayano
AU - Miyawaki, Kohta
AU - Takenaka, Katsuto
AU - Iwasaki, Hiromi
AU - Akashi, Koichi
N1 - Funding Information:
This study was supported in part by a Grant-in-Aid for Young Scientists (A) (to Y.K., no. 26713034), a Grant-in-Aid for Scientific Research on Innovative Areas “Development of Novel Treatment Strategies Targeting Cancer Stem Cells” (to K.A. no., 22130001 and 22130002) and “Stem Cell Aging and Disease” (to T.M., no. 25115002), a Grant-in-Aid for JSPS fellows (to Y.K.), a Grant-in-Aid for Scientific Research (A) (to K.A., no. 25253069), a Grant-in-Aid for Scientific Research (B) (to T.M., no. 23390254), and a Grant-in-Aid from Japan intractable diseases research foundation (to Y.K.). This study was also supported in part by a contribution from Chiyu-Kai and by a grant from Kyowa Hakko Kirin Co., Ltd., and S.-i.T. is an employee of Kyowa Hakko Kirin Co., Ltd.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/9/3
Y1 - 2015/9/3
N2 - 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.
AB - 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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U2 - 10.1016/j.stem.2015.07.011
DO - 10.1016/j.stem.2015.07.011
M3 - Article
C2 - 26279267
AN - SCOPUS:84941023046
SN - 1934-5909
VL - 17
SP - 341
EP - 352
JO - Cell stem cell
JF - Cell stem cell
IS - 3
M1 - 1815
ER -