Hes1 suppresses acute myeloid leukemia development through FLT3 repression

Kato, Takumi; Sakata‐Yanagimoto, Mamiko; Nishikii, Hidekazu; Ueno, Masaya; Miyake, Yasuyuki; Yokoyama, Yasuhisa; Asabe, Y; Kamada, Yusuke; Muto, Hideharu; Obara, Naoshi; Suzukawa, Kazumi; Hasegawa, Yoshimi; Kitabayashi, Issay; Uchida, Koichiro; Hirao, Atsushi; Yagita, Hideo; Kageyama, Ryoichiro

doi:10.1038/leu.2014.281

Cited by 36 publications

(30 citation statements)

References 48 publications

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“…Curiously, the expression of several Notch-related genes, including Hes1, a known downstream target of Notch signaling, was increased after TKI exposure in both FLT3/ITD + AML primary samples and cell lines. Notably, Takayasu Kato et al 31 reported that Hes1 binds directly to the promoter region of the FLT3 gene and downregulates promoter activity. It has also been reported that the Hes1 protein directly binds to STAT3 and promotes STAT3 phosphorylation and activation.…”

Section: Discussionmentioning

confidence: 99%

Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

Li¹,

Li²,

Shang³

et al. 2020

Sig Transduct Target Ther

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Internal tandem duplication (ITD) mutations of FMS-like tyrosine kinase-3 (FLT3) are the most frequent genetic alterations in acute myeloid leukemia (AML) and predict a poor prognosis. FLT3 tyrosine kinase inhibitors (TKIs) provide short-term clinical responses, but the long-term prognosis of FLT3/ITD + AML patients remains poor. Notch signaling is important in numerous types of tumors. However, the role of Notch signaling in FLT3/ITD + AML remains to be elucidated. In the current study, we found that Notch signaling was activated upon FLT3-TKI treatment in FLT3/ITD + cell lines and primary cells. As Notch signaling can be blocked by γ-secretase inhibitors (GSIs), we examined the combinatorial antitumor efficacy of FLT3-TKIs and GSIs against FLT3/ITD + AML and explored the underlying molecular mechanisms. As a result, we observed synergistic cytotoxic effects, and the treatment preferentially reduced cell proliferation and induced apoptosis in FLT3/ITD + AML cell lines and in primary AML cells. Furthermore, the combination of FLT3-TKI and GSI eradicated leukemic cells and prolonged survival in an FLT3/ITD + patient-derived xenograft AML model. Mechanistically, differential expression analysis suggested that CXCR3 may be partially responsible for the observed synergy, possibly through ERK signaling. Our findings suggest that combined therapies of FLT3-TKIs with GSI may be exploited as a potential therapeutic strategy to treat FLT3/ITD + AML.

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Section: Discussionmentioning

confidence: 99%

Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

Li¹,

Li²,

Shang³

et al. 2020

Sig Transduct Target Ther

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“…Previous studies described the poor activation of Notch in AML samples [11, 12, 28]. Nevertheless, accumulating evidence highlighted the role of Notch in the interaction between bone marrow microenvironment and leukemia cells by showing that hBM-MSCs are capable of inducing activation of Notch signalling in different cancer cells, including multiple myeloma, CLL, and T-ALL [4, 5, 29, 30].…”

Section: Discussionmentioning

confidence: 99%

Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia

et al. 2016

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Both preclinical and clinical investigations suggest that Notch signalling is critical for the development of many cancers and for their response to chemotherapy. We previously showed that Notch inhibition abrogates stromal-induced chemoresistance in lymphoid neoplasms. However, the role of Notch in acute myeloid leukemia (AML) and its contribution to the crosstalk between leukemia cells and bone marrow stromal cells remain controversial. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML cells in co-culture with bone marrow mesenchymal stromal cells expanded from both healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*). As compared to hBM-MSCs, hBM-MSCs* showed higher level of Notch1, Jagged1 as well as the main Notch target gene HES1. Notably, hBM-MSCs* induced expression and activation of Notch signalling in AML cells, supporting AML proliferation and being more efficientin inducing AML chemoresistance than hBM-MSCs*. Pharmacological inhibition of Notch using combinations of Notch receptor-blocking antibodies or gamma-secretase inhibitors (GSIs), in presence of chemotherapeutic agents, significant lowered the supportive effect of hBM-MSCs and hBM-MSCs* towards AML cells, by activating apoptotic cascade and reducing protein level of STAT3, AKT and NF-κB.These results suggest that Notch signalling inhibition, by overcoming the stromal-mediated promotion of chemoresistance,may represent a potential therapeutic targetnot only for lymphoid neoplasms, but also for AML.

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“…It has been reported that HES1 was involved in cell cycle, and maintained multipotent precursor cells in an undifferentiated state in several tissues during development and adulthood [22]. Recently, it was reported that HES1 acted as a tumor suppressor in MLL-AF9 AML mice model [10].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies found that overexpression of HES1 inhibited cycling of hematopoietic stem and progenitor cells (HSPCs) in vitro and cell expansion in vivo, associated with upregulation of p21 [9]. Recently, it was reported that HES1 acted as a tumor suppressor in MLL-AF9 AML mice model [10]. But the role of HES1 in primary AML cells with other gene mutations and AML cell lines has not been well demonstrated.…”

Section: Introductionmentioning

confidence: 98%

HES1 activation suppresses proliferation of leukemia cells in acute myeloid leukemia

Tian

Jia

et al. 2015

Ann Hematol

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Although aberrant Notch activation contributes to leukemogenesis in T cells, the role of Notch pathway in acute myeloid leukemia (AML) remains controversial. To address this issue, we compared the expression levels of its downstream effector HES1 and p21 in bone marrow mononuclear cells (BMNCs) from 30 newly diagnosed AML patients and three AML cell lines to normal BMNCs. The results showed that both of them were downregulated in AML cells. In vitro, induced activation of HES1 by retrovirus in AML cell lines consistently led to AML cell growth arrest and apoptosis induction, which was associated with enhanced p21 expression. Furthermore, overexpression of HES1 in primary AML cells inhibited growth of AML in a xenograft mice model. In conclusion, we demonstrated the tumor suppressor role of HES1 in AML.

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Hes1 suppresses acute myeloid leukemia development through FLT3 repression

Cited by 36 publications

References 48 publications

Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia

HES1 activation suppresses proliferation of leukemia cells in acute myeloid leukemia

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