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Hes1 Controls Proliferation and Apoptosis in Chronic Lymphoblastic Leukemia Cells by Modulating PTEN Expression

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Abstract

Hairy and enhancer of split homolog-1 (HES1), regulated by the Notch, has been reported to play important roles in the immune response and cancers, such as leukemia. In this study, we aim to explore the effect of HES1-mediated Notch1 signaling pathway in chronic lymphocytic leukemia (CLL). Reverse transcription quantitative polymerase chain reaction and Western blot assay were conducted to determine the expression of HES1, Notch1, and PTEN in B lymphocytes of peripheral blood samples of 60 CLL patients. We used lentivirus-mediated overexpression or silencing of HES1 and the Notch1 signaling pathway inhibitor, MW167, to detect the interaction among HES1, Notch1, and PTEN in CLL MEC1 and HG3 cells. MTT assay and flow cytometry were employed for detection of biological behaviors of CLL cells. HES1 and Notch1 showed high expression, but PTEN displayed low expression in B lymphocytes of peripheral blood samples of patients with CLL in association with poor prognosis. HES1 bound to the promoter region of PTEN and reduced PTEN expression. Overexpression of HES1 activated the Notch1 signaling pathway, thus promoting the proliferation of CLL cells, increasing the proportion of cells arrested at the S phase and limiting the apoptosis of CLL cells. Collectively, HES1 can promote activation of the Notch1 signaling pathway to cause PTEN transcription inhibition and the subsequent expression reduction, thereby promoting the proliferation and inhibiting the apoptosis of CLL cells.

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Funding

This study was funded by the General items of Health Department of Zhejiang Province (2021KY1078), the Zhejiang Provincial Health Science and Technology Plan in 2022 (Clinical Research Application Project) (2022KY350), and the Wenzhou Science and Technology Bureau (Y20210155).

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  1. Qikai Zhang and Zongsi Zhu have contributed equally to this work.

Authors and Affiliations

  1. Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China

    Qikai Zhang, Zongsi Zhu & Jiaqiang Guan

  2. Department of Haematology and Chemotherapy, Wenzhou Central Hospital, Theorem Clinical College of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China

    Yingying Hu, Bijing Lin, Shanshan Weng, Yuemiao Chen & Cuiping Zheng

  3. Department of Chemotherapy, Cancer Hospital of The University of Chinese Academy of Science, Wenzhou Campus, Wenzhou, 325000, People’s Republic of China

    Wenjin Zhou & Wanchun Ye

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  1. Qikai Zhang
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Contributions

CZ and WZ conceived and designed research. WY performed experiments. BL interpreted results of experiments. SW analyzed data. YC prepared figures. QZ performed the bioinformatics analysis and drafted paper. JG, ZZ, and YH edited and revised the manuscript. All authors read and approved final version of manuscript.

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Correspondence to Cuiping Zheng.

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12033_2022_476_MOESM1_ESM.jpg

Supplementary file1 (DOCX 1499 KB). Supplementary Figure 1. Bioinformatics prediction of HES1-related signaling pathways in CLL. A, HES1-related signaling pathways predicted by the Wikipathways website. B, Protein–protein interaction network of the top 30 differentially expressed genes in the GSE26725 dataset analyzed on STRING.

12033_2022_476_MOESM2_ESM.jpg

Supplementary file2 (DOCX 429 KB). Supplementary Figure 2. The highest expression of HES1 in the MEC1 cell line and the lowest in the HG3 cell line. A, HES1 mRNA expression in CLL-AAT, MEC2, 183-E95, MEC1, and HG3 cell lines determined by RT-qPCR. B, NOTCH1 and PTEN mRNA expression in MEC1 and HG3 cell lines determined by RT-qPCR. *p < 0.05 vs. CLL-AAT cells. #p < 0.05 vs. MEC1 cell line. The experiment was repeated 3 times independently.

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Zhang, Q., Zhu, Z., Guan, J. et al. Hes1 Controls Proliferation and Apoptosis in Chronic Lymphoblastic Leukemia Cells by Modulating PTEN Expression. Mol Biotechnol 64, 1419–1430 (2022). https://doi.org/10.1007/s12033-022-00476-2

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