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

Research output: Contribution to journalArticle

65 Citations (Scopus)

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.

Original languageEnglish
Article number1815
Pages (from-to)341-352
Number of pages12
JournalCell stem cell
Volume17
Issue number3
DOIs
Publication statusPublished - Sep 3 2015

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Cell Biology

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