Elevated TIM3+ hematopoietic stem cells in untreated myelodysplastic syndrome displayed aberrant differentiation, overproliferation and decreased apoptosis

Tao, Jinglian; Li, Lijuan; Fu, Rong; Wang, Huaquan; Jiang, Huijuan; Yue, Lanzhu; Zhang, Wei; Liu, Hui; Ruan, Erbao; Qu, Wen; Wang, Guojin; Wang, Xiaoming; Wu, Yuhong; Hong, Liu; Song, Jia; Guan, Jing; Xing, Limin; Shao, Zonghong

doi:10.1016/j.leukres.2014.03.018

Cited by 23 publications

(30 citation statements)

References 24 publications

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“…Previous report showed that TIM3+ HSCs with higher GATA2 displayed overproliferation and decreased apoptosis [33]. Our result confirmed that the increased apoptosis appeared in KG1a cells with knocking down GATA2.…”

Section: Discussionsupporting

confidence: 90%

GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy

et al. 2017

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Drug resistance constitutes one of the main obstacles for clinical recovery of acute myeloid leukemia (AML) patients. Therefore, the treatment of AML requires new strategies, such as adding a third drug. To address whether GATA2 could act as a regulator of chemotherapy resistance in human leukemia cells, we observed KG1a cells and clinical patients’ AML cells with a classic drug (Cerubidine) and Gefitinib. After utilizing chemotherapy, the expression of GATA2 and its target genes (EVI, SCL and WT1) in surviving AML cells and KG1a cells were significantly enhanced to double and quadrupled compared to its original level respectively. Furthermore, with continuous chemotherapeutics, AML cells with GATA2 knockdown or treated with GATA2 inhibitor (K1747) almost eliminated with dramatically reduced expression of WT1, SCL, EVI, and significantly increased apoptotic population. Therefore, we propose that reducing GATA2 expression or inhibition of its transcription activity can relieve the drug resistance of acute myeloid leukemia cells and it would be helpful for eliminating the leukemia cells in patients.

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Section: Discussionsupporting

confidence: 90%

GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy

et al. 2017

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“…Additionally, high doses of ATO cause intolerable toxicity (12). Furthermore, MDS, as a pre-leukemia status, exhibits the characteristics of leukemia transformation and relapse, which may be closely associated with pre-leukemic stem cells (pre-LSCs) and leukemic stem cells (LSCs) (13,14). Effective killing of MDS cells, as well as pre-LSCs and LSCs, by combining ATO with a chemosensitizer may be a potential strategy to improve the response rate of MDS patients to ATO treatment, block leukemic transformation and prevent MDS relapse.…”

Section: Introductionmentioning

confidence: 99%

Curcumin reduces the expression of survivin, leading to enhancement of arsenic trioxide-induced apoptosis in myelodysplastic syndrome and leukemia stem-like cells

et al. 2016

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Low response, treatment-related complications and relapse due to the low sensitivity of myelodysplastic syndrome (MDS) and leukemia stem cells (LSCs) or pre-LSCs to arsenic trioxide (ATO), represent the main problems following treatment with ATO alone in patients with MDS. To solve these problems, a chemosensitization agent can be applied to increase the susceptibility of these cells to ATO. Curcumin (CUR), which possesses a wide range of anticancer activities, is a commonly used chemosensitization agent for various types of tumors, including hematopoietic malignancies. In the present study, we investigated the cytotoxic effects and potential mechanisms in MDS-SKM-1 and leukemia stem-like KG1a cells treated with CUR and ATO alone or in combination. CUR and ATO exhibited growth inhibition detected by MTT assays and apoptosis analyzed by Annexin V/PI analyses in both SKM-1 and KG1a cells. Apoptosis of SKM-1 and KG1a cells determined by Annexin V/PI was significantly enhanced in the combination groups compared with the groups treated with either agent alone. Further evaluation was performed by western blotting for two hallmark markers of apoptosis, caspase-3 and cleaved-PARP. Co-treatment of the cells with CUR and ATO resulted in significant synergistic effects. In SKM-1 and KG1a cells, 31 and 13 proteins analyzed by protein array assays were modulated, respectively. Notably, survivin protein expression levels were downregulated in both cell lines treated with CUR alone and in combination with ATO, particularly in the latter case. Susceptibility to apoptosis was significantly increased in SKM-1 and KG1a cells treated with siRNA-survivin and ATO. These results suggested that CUR increased the sensitivity of SKM-1 and KG1a cells to ATO by downregulating the expression of survivin.

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“…Increasing malignant clones and cellular immunity defects are involved in the pathogenesis of MDS, which is a malignant haematological disease. Daver et al found that the efficacy of hypomethylating agent combination with immune checkpoint inhibitors (PD‐1 inhibitor) in MDS was better than hypomethylating agents alone.…”

Section: Discussionmentioning

confidence: 99%

“…Myelodysplastic syndromes (MDS) are malignant bone marrow disorders characterized by ineffective haematopoiesis and high risk to transformation into acute myeloid leukaemia. Increased malignant clones and cellular immunodeficiency might contribute to the pathogenesis of MDS . Cytotoxic T lymphocytes (CTLs) play a central role in tumour immunity .…”

Section: Introductionmentioning

confidence: 99%

“…CD8 + T cells with less INF‐γ overexpressed TIM3 in MDS patients. Further, TIM3 + CD8 + T cells produce less perforin and granzyme B . The hypothesis that CD8 + T cells exhaustion might be induced by MDSCs through TIM3/Gal‐9 pathway drove us to detect Gal‐9 expression in MDSCs, and the level of perforin and granzyme B in CD8 + T cells after co‐culture with MDSCs or excess exogenous Gal‐9 or TIM3/Gal‐9 pathway inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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CD8⁺ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway

Tao

Han

Gao

et al. 2019

J Cellular Molecular Medi

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CD8+ T cells play a central role in antitumour immunity, which often exhibit ‘exhaustion’ in the setting of malignancy and chronic viral infection due to T cell immunoglobulin and mucin domain 3 (TIM3) and myeloid‐derived suppressor cells (MDSCs). Our team previously found that overactive MDSCs and exhausted TIM3+CD8+ T cells were observed in myelodysplastic syndromes (MDS) patients. However, it is not obvious whether MDSCs suppress CD8+ T cells through TIM3/Gal‐9 pathway. Here, Gal‐9, as the ligand of TIM3, was overexpressed in MDSCs. The levels of Gal‐9 in bone marrow supernatants, serum and culture supernatants of MDSCs from MDS patients were elevated. CD8+ T cells from MDS or normal controls produced less perforin and granzyme B and exhibited increased early apoptosis after co‐culture with MDSCs from MDS. Meanwhile, the cytokines produced by CD8+ T cells could be partially restored by TIM3/Gal‐9 pathway inhibitors. Furthermore, CD8+ T cells produced less perforin and granzyme B after co‐culture with excess exogenous Gal‐9, and the function of CD8+ T cells was similarly restored by TIM3/Gal‐9 pathway inhibitors. Expression of Notch1, EOMES (associated with perforin and granzyme B secretion), p‐mTOR and p‐AKT (associated with cell proliferation) was decreased in CD8+ T cells from MDS after co‐culture with excess exogenous Gal‐9. These suggested that MDSCs might be the donor of Gal‐9, and TIM3/Gal‐9 pathway might be involved in CD8+ T cells exhaustion in MDS, and that TIM3/Gal‐9 pathway inhibitor might be the promising candidate for target therapy of MDS in the future.

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Elevated TIM3+ hematopoietic stem cells in untreated myelodysplastic syndrome displayed aberrant differentiation, overproliferation and decreased apoptosis

Cited by 23 publications

References 24 publications

GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy

GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy

Curcumin reduces the expression of survivin, leading to enhancement of arsenic trioxide-induced apoptosis in myelodysplastic syndrome and leukemia stem-like cells

CD8⁺ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway

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Elevated TIM3+ hematopoietic stem cells in untreated myelodysplastic syndrome displayed aberrant differentiation, overproliferation and decreased apoptosis

Cited by 23 publications

References 24 publications

GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy

GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy

Curcumin reduces the expression of survivin, leading to enhancement of arsenic trioxide-induced apoptosis in myelodysplastic syndrome and leukemia stem-like cells

CD8+ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway

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CD8⁺ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway