Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C

Abstract Acute myeloid leukemia (AML) is a deadly cancer characterized by an expanded self-renewal capacity that is associated with the accumulation of immature myeloid cells. Emerging evidence shows that methyl-CpG-binding domain protein 2 (MBD2), a DNA methylation reader, often participates in the...

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Autores principales:	Kuangguo Zhou, Mi Zhou, Ling Cheng, Xing Chen, Xiaomin Wang, Yajing Chu, Qilin Yu, Shu Zhang, Na Wang, Lei Zhao, Di Wang, Liang Huang, Congyi Wang, Weiping Yuan, Jianfeng Zhou
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/e57105c321a641b28faba3c774324d47
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spelling	oai:doaj.org-article:e57105c321a641b28faba3c774324d472021-11-21T12:15:20ZLoss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C10.1038/s41389-021-00366-32157-9024https://doaj.org/article/e57105c321a641b28faba3c774324d472021-11-01T00:00:00Zhttps://doi.org/10.1038/s41389-021-00366-3https://doaj.org/toc/2157-9024Abstract Acute myeloid leukemia (AML) is a deadly cancer characterized by an expanded self-renewal capacity that is associated with the accumulation of immature myeloid cells. Emerging evidence shows that methyl-CpG-binding domain protein 2 (MBD2), a DNA methylation reader, often participates in the transcriptional silencing of hypermethylated genes in cancer cells. Nevertheless, the role of MBD2 in AML remains unclear. Herein, by using an MLL-AF9 murine model and a human AML cell line, we observed that loss of MBD2 could delay the initiation and progression of leukemia. MBD2 depletion significantly reduced the leukemia burden by decreasing the proportion of leukemic stem cells (LSCs) and inhibiting leukemia cell proliferation in serial transplantation experiments, thereby allowing leukemic blasts to transition to a more mature state reflecting normal myelopoiesis. Both gene expression analyses and bioinformatic studies revealed that MBD2 negatively modulated genes related to myeloid differentiation, and was necessary to sustain the MLL-AF9 oncogene-induced gene program. We further demonstrated that MBD2 could promote LSC cell cycle progression through epigenetic regulation of CDKN1C transcription probably by binding to its promoter region. Taken together, our data suggest that MBD2 promotes AML development and could be a therapeutic target for myeloid malignancies.Kuangguo ZhouMi ZhouLing ChengXing ChenXiaomin WangYajing ChuQilin YuShu ZhangNa WangLei ZhaoDi WangLiang HuangCongyi WangWeiping YuanJianfeng ZhouNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncogenesis, Vol 10, Iss 11, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Kuangguo Zhou Mi Zhou Ling Cheng Xing Chen Xiaomin Wang Yajing Chu Qilin Yu Shu Zhang Na Wang Lei Zhao Di Wang Liang Huang Congyi Wang Weiping Yuan Jianfeng Zhou Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C
description	Abstract Acute myeloid leukemia (AML) is a deadly cancer characterized by an expanded self-renewal capacity that is associated with the accumulation of immature myeloid cells. Emerging evidence shows that methyl-CpG-binding domain protein 2 (MBD2), a DNA methylation reader, often participates in the transcriptional silencing of hypermethylated genes in cancer cells. Nevertheless, the role of MBD2 in AML remains unclear. Herein, by using an MLL-AF9 murine model and a human AML cell line, we observed that loss of MBD2 could delay the initiation and progression of leukemia. MBD2 depletion significantly reduced the leukemia burden by decreasing the proportion of leukemic stem cells (LSCs) and inhibiting leukemia cell proliferation in serial transplantation experiments, thereby allowing leukemic blasts to transition to a more mature state reflecting normal myelopoiesis. Both gene expression analyses and bioinformatic studies revealed that MBD2 negatively modulated genes related to myeloid differentiation, and was necessary to sustain the MLL-AF9 oncogene-induced gene program. We further demonstrated that MBD2 could promote LSC cell cycle progression through epigenetic regulation of CDKN1C transcription probably by binding to its promoter region. Taken together, our data suggest that MBD2 promotes AML development and could be a therapeutic target for myeloid malignancies.
format	article
author	Kuangguo Zhou Mi Zhou Ling Cheng Xing Chen Xiaomin Wang Yajing Chu Qilin Yu Shu Zhang Na Wang Lei Zhao Di Wang Liang Huang Congyi Wang Weiping Yuan Jianfeng Zhou
author_facet	Kuangguo Zhou Mi Zhou Ling Cheng Xing Chen Xiaomin Wang Yajing Chu Qilin Yu Shu Zhang Na Wang Lei Zhao Di Wang Liang Huang Congyi Wang Weiping Yuan Jianfeng Zhou
author_sort	Kuangguo Zhou
title	Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C
title_short	Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C
title_full	Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C
title_fullStr	Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C
title_full_unstemmed	Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C
title_sort	loss of mbd2 attenuates mll-af9-driven leukemogenesis by suppressing the leukemic cell cycle via cdkn1c
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/e57105c321a641b28faba3c774324d47
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Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C

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