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

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

doi:10.1016/j.stem.2015.07.011

Cited by 222 publications

(216 citation statements)

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“…It has been reported to specifically interact with the immune receptor Tim-3 inducing mTOR pathway activation as well as forming an autocrine loop with Tim-3 in human AML cells 3,5 . Due to very high expression levels of Tim-3 in AML cells this protein is currently considered as a target for anti-AML therapy.…”

Section: Resultsmentioning

confidence: 99%

“…Although the biochemical activities of Tim-3 have recently been elucidated, 3-7 the functional role of this protein/receptor in AML cells remains unclear and the reasons for striking increases in Tim-3 levels in these cells are also not yet understood. Galectin-9, which was found to be a natural Tim-3 ligand, 3,5 was recently suggested to form an autocrine loop, where newly released galectin-9 interacts with Tim-3 expressed on the cell surface 3 . Furthermore, in leukocytes Tim-3 is known to be shed by proteolytic enzymes including metalloproteinases 8 .…”

Section: Introductionmentioning

confidence: 99%

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The immune receptor Tim-3 acts as a trafficker in a Tim-3/galectin-9 autocrine loop in human myeloid leukemia cells

et al. 2016

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The immune receptor Tim-3 is often highly expressed in human acute myeloid leukemia (AML) cells where it acts as a growth factor and inflammatory receptor. Recently, it has been demonstrated that Tim-3 forms an autocrine loop with its natural ligand galectin-9 in human AML cells. However, the pathophysiological functions of Tim-3 in human AML cells remain unclear. Here, we report for the first time that Tim-3 is required for galectin-9 secretion in human AML cells. However, this effect is cell-type specific and was found so far to be applicable only to myeloid (and not, for example, lymphoid) leukemia cells. We concluded that AML cells might use Tim-3 as a trafficker for the secretion of galectin-9 which can then be possibly used to impair the anticancer activities of cytotoxic T cells and natural killer (NK) cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The immune receptor Tim-3 acts as a trafficker in a Tim-3/galectin-9 autocrine loop in human myeloid leukemia cells

et al. 2016

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“…Of particular interest is the upregulation of galectin-9 (LGALS9), which is the ligand for TIM-3 [40]. LGALS9 can exert pleiotropic effects through TIM-3, and it has been shown to promote leukemic stem cell renewal, suggesting that this gene that appears to be up-regulated by the process of immune reconstitution after chemotherapy may also have a role in AML relapse [41, 42]. …”

Section: Discussionmentioning

confidence: 99%

Impaired B cell immunity in acute myeloid leukemia patients after chemotherapy

et al. 2017

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BackgroundChanges in adaptive immune cells after chemotherapy in adult acute myeloid leukemia (AML) may have implications for the success of immunotherapy. This study was designed to determine the functional capacity of the immune system in adult patients with AML who have completed chemotherapy and are potential candidates for immunotherapy.MethodsWe used the response to seasonal influenza vaccination as a surrogate for the robustness of the immune system in 10 AML patients in a complete remission post-chemotherapy and performed genetic, phenotypic, and functional characterization of adaptive immune cell subsets.ResultsOnly 2 patients generated protective titers in response to vaccination, and a majority of patients had abnormal frequencies of transitional and memory B-cells. B-cell receptor sequencing showed a B-cell repertoire with little evidence of somatic hypermutation in most patients. Conversely, frequencies of T-cell populations were similar to those seen in healthy controls, and cytotoxic T-cells demonstrated antigen-specific activity after vaccination. Effector T-cells had increased PD-1 expression in AML patients least removed from chemotherapy.ConclusionOur results suggest that while some aspects of cellular immunity recover quickly, humoral immunity is incompletely reconstituted in the year following intensive cytotoxic chemotherapy for AML. The observed B-cell abnormalities may explain the poor response to vaccination often seen in AML patients after chemotherapy. Furthermore, the uncoupled recovery of B-cell and T-cell immunity and increased PD-1 expression shortly after chemotherapy might have implications for the success of several modalities of immunotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1252-2) contains supplementary material, which is available to authorized users.

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“…This process is named autocrine or paracrine mechanisms. 35 Sustained proliferation leads to a greater mutation possibility. Thus, mutation is one of the main factors in leukemia initiation and progression.…”

Section: Leukemia Pathogenesismentioning

confidence: 99%

Melatonin: A promising agent targeting leukemia

Shafabakhsh

Mirzaei

Asemi

2019

J of Cellular Biochemistry

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Leukemia or cancer of blood is a well‐known cancer, which affects a range of people from newborns to the very old. It is a public health problem throughout the world. By way of treatment, due to the lack of specific anticancer therapies, common treatments of leukemia lead to severe side effects. Nonspecific anticancer drugs result in inhibition of normal cell growth and thereby their necrosis. Moreover, drug resistance is an additional problem, which stands in the way of leukemia treatment. Thus, finding new treatments for leukemia is essential. Melatonin, as a natural product, has been shown to be effective in a wide variety of diseases such as coronary heart disease, schizophrenia, chronic pain, and Alzheimer's disease. In addition, melatonin levels have been observed to be altered in different cancers, such as breast cancer, colorectal cancer endometrial cancer, and hematopoetical cancers. Anticancer features of melatonin such as pro‐oxidation, apoptosis induction, antiangiogenesis property and metastasis and invasion inhibition suggest that this natural compound can be used as a potential agent in novel therapeutic strategies for cancers. Also, it has been reported that melatonin has positive and protective effects on different physiological reactions and in normal bone marrow cells suggesting effectiveness in leukemia therapy. Thus, the aim of our paper was to depict and summarize the main molecular targets of melatonin on leukemia models.

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

Cited by 222 publications

References 57 publications

The immune receptor Tim-3 acts as a trafficker in a Tim-3/galectin-9 autocrine loop in human myeloid leukemia cells

The immune receptor Tim-3 acts as a trafficker in a Tim-3/galectin-9 autocrine loop in human myeloid leukemia cells

Impaired B cell immunity in acute myeloid leukemia patients after chemotherapy

Melatonin: A promising agent targeting leukemia

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