Loss of Asxl2 leads to myeloid malignancies in mice

Jianping Li, Fuhong He, Peng Zhang, Shi Chen, Hui Shi, Yanling Sun, Ying Guo, Hui Yang, Na Man, Sarah Greenblatt, Zhaomin Li, Zhengyu Guo, Yuan Zhou, Lan Wang, LLuis Morey, Sion Llewelyn Williams, Xi Chen, Qun Tian Wang, Stephen D Nimer, Peng YuQian Fei Wang, Mingjiang Xu, Feng-Chun Yang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

ASXL2 is frequently mutated in acute myeloid leukaemia patients with t(8;21). However, the roles of ASXL2 in normal haematopoiesis and the pathogenesis of myeloid malignancies remain unknown. Here we show that deletion of Asxl2 in mice leads to the development of myelodysplastic syndrome (MDS)-like disease. Asxl2-/- mice have an increased bone marrow (BM) long-term haematopoietic stem cells (HSCs) and granulocyte-macrophage progenitors compared with wild-type controls. Recipients transplanted with Asxl2-/- and Asxl2+/- BM cells have shortened lifespan due to the development of MDS-like disease or myeloid leukaemia. Paired daughter cell assays demonstrate that Asxl2 loss enhances the self-renewal of HSCs. Deletion of Asxl2 alters the expression of genes critical for HSC self-renewal, differentiation and apoptosis in Lin ' cKit + cells. The altered gene expression is associated with dysregulated H3K27ac and H3K4me1/2. Our study demonstrates that ASXL2 functions as a tumour suppressor to maintain normal HSC function.

Original languageEnglish (US)
Article number15456
JournalNature Communications
Volume8
DOIs
StatePublished - Jun 8 2017

Fingerprint

stem cells
Hematopoietic Stem Cells
Stem cells
mice
deletion
leukemias
bone marrow
Myelodysplastic Syndromes
Neoplasms
Bone
hematopoiesis
cells
Gene Expression
suppressors
pathogenesis
Granulocyte-Macrophage Progenitor Cells
Myeloid Leukemia
macrophages
Macrophages
gene expression

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Loss of Asxl2 leads to myeloid malignancies in mice. / Li, Jianping; He, Fuhong; Zhang, Peng; Chen, Shi; Shi, Hui; Sun, Yanling; Guo, Ying; Yang, Hui; Man, Na; Greenblatt, Sarah; Li, Zhaomin; Guo, Zhengyu; Zhou, Yuan; Wang, Lan; Morey, LLuis; Williams, Sion Llewelyn; Chen, Xi; Wang, Qun Tian; Nimer, Stephen D; Yu, Peng; Wang, Qian Fei; Xu, Mingjiang; Yang, Feng-Chun.

In: Nature Communications, Vol. 8, 15456, 08.06.2017.

Research output: Contribution to journalArticle

Li, J, He, F, Zhang, P, Chen, S, Shi, H, Sun, Y, Guo, Y, Yang, H, Man, N, Greenblatt, S, Li, Z, Guo, Z, Zhou, Y, Wang, L, Morey, LL, Williams, SL, Chen, X, Wang, QT, Nimer, SD, Yu, P, Wang, QF, Xu, M & Yang, F-C 2017, 'Loss of Asxl2 leads to myeloid malignancies in mice', Nature Communications, vol. 8, 15456. https://doi.org/10.1038/ncomms15456
Li J, He F, Zhang P, Chen S, Shi H, Sun Y et al. Loss of Asxl2 leads to myeloid malignancies in mice. Nature Communications. 2017 Jun 8;8. 15456. https://doi.org/10.1038/ncomms15456
Li, Jianping ; He, Fuhong ; Zhang, Peng ; Chen, Shi ; Shi, Hui ; Sun, Yanling ; Guo, Ying ; Yang, Hui ; Man, Na ; Greenblatt, Sarah ; Li, Zhaomin ; Guo, Zhengyu ; Zhou, Yuan ; Wang, Lan ; Morey, LLuis ; Williams, Sion Llewelyn ; Chen, Xi ; Wang, Qun Tian ; Nimer, Stephen D ; Yu, Peng ; Wang, Qian Fei ; Xu, Mingjiang ; Yang, Feng-Chun. / Loss of Asxl2 leads to myeloid malignancies in mice. In: Nature Communications. 2017 ; Vol. 8.
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abstract = "ASXL2 is frequently mutated in acute myeloid leukaemia patients with t(8;21). However, the roles of ASXL2 in normal haematopoiesis and the pathogenesis of myeloid malignancies remain unknown. Here we show that deletion of Asxl2 in mice leads to the development of myelodysplastic syndrome (MDS)-like disease. Asxl2-/- mice have an increased bone marrow (BM) long-term haematopoietic stem cells (HSCs) and granulocyte-macrophage progenitors compared with wild-type controls. Recipients transplanted with Asxl2-/- and Asxl2+/- BM cells have shortened lifespan due to the development of MDS-like disease or myeloid leukaemia. Paired daughter cell assays demonstrate that Asxl2 loss enhances the self-renewal of HSCs. Deletion of Asxl2 alters the expression of genes critical for HSC self-renewal, differentiation and apoptosis in Lin ' cKit + cells. The altered gene expression is associated with dysregulated H3K27ac and H3K4me1/2. Our study demonstrates that ASXL2 functions as a tumour suppressor to maintain normal HSC function.",
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