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

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

来源：Cell Stem Cell, 2015, 17(3): 341-352.

DOI：10.1016/j.stem.2015.07.011

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-kappa B and beta-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.

• 出版日期2015-9