A TIM-3/galectin-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemia progression

KIKUSHIGE Yoshikane

doi:10.11406/rinketsu.57.412

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TIM-3/galectin-9によるautocrine loopは骨髄系白血病幹細胞の自己複製を強化し白血病進展に寄与する
TIM-3/galectin-9 ニヨル autocrine loop ワコツズイケイハッケツビョウカンサイボウノジコフクセイオキョウカシハッケツビョウシンテンニキヨスル

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Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. We previously reported that the T-cell immunoglobulin mucin-3 (TIM-3) is expressed on the LCS surface in most types of AML. Since only the TIM-3⁺, i.e. not the TIM-3^-, fraction of human AML cells can reconstitute human AML in immunodeficient mice, we hypothesized that the TIM-3 has an essential function in maintaining AML LSCs. Herein, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for human AML LSC development. Serum Gal-9 was significantly elevated in primary AML patients and in mice xenografted with human AML. Neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML, as well as Gal-9 ligation of TIM-3 co-activated NF-κB and β-catenin signaling, suggesting that TIM-3 signaling is necessary for LSC self-renewal. Interestingly, identical changes were found to be involved in the progressive transformation of a variety of pre-leukemic disorders into myeloid leukemia. Thus, molecules constituting the TIM-3/Gal-9 autocrine loop are potential therapeutic targets applicable to most types of myeloid leukemia.

Journal

Rinsho Ketsueki

Rinsho Ketsueki 57 (4), 412-416, 2016

The Japanese Society of Hematology

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