Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice

Jiapeng Wang, Zhaomin Li, Yongzheng He, Feng Pan, Shi Chen, Steven Rhodes, Lihn Nguyen, Jin Yuan, Li Jiang, Xianlin Yang, Ophelia Weeks, Ziyue Liu, Jiehao Zhou, Hongyu Ni, Chen Leng Cai, Mingjiang Xu, Feng Chun Yang

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

ASXL1 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies, and its alterations are associated with poor prognosis. De novo ASXL1 mutations cause Bohring-Opitz syndrome characterized by multiple congenital malformations. We show that Asxl1 deletion in mice led to developmental abnormalities including dwarfism, anophthalmia, and 80%embryonic lethality. Surviving Asxl1-/- mice lived for up to 42 days and developed features of myelodysplastic syndrome (MDS), including dysplastic neutrophils and multiple lineage cytopenia. Asxl1-/- mice had a reduced hematopoietic stem cell (HSC) pool, and Asxl1-/- HSCs exhibited decreased hematopoietic repopulating capacity, with skewed cell differentiation favoring granulocytic lineage. Asxl1+/-mice also developed mild MDS-like disease, which could progress to MDS/myeloproliferative neoplasm, demonstrating a haploinsufficient effect of Asxl1 in the pathogenesis of myeloid malignancies. Asxl1 loss led to an increased apoptosis andmitosis in Lineage-c-Kit+ (Lin-c-Kit+) cells, consistent with humanMDS. Furthermore, Asxl1-/- Lin -c-Kit+ cells exhibited decreased global levels of H3K27me3 and H3K4me3 and altered expression of genes regulating apoptosis (Bcl2, Bcl2l12, Bcl2l13). Collectively, we report a novel ASXL1 murine model that recapitulates human myeloid malignancies, implying that Asxl1 functions as a tumor suppressor to maintain hematopoietic cell homeostasis. Future work is necessary to clarify the contribution of microenvironment to the hematopoietic phenotypes observed in the constitutional Asxl-/- mice.

Original languageEnglish (US)
Pages (from-to)541-553
Number of pages13
JournalBlood
Volume123
Issue number4
DOIs
StatePublished - Jan 23 2014

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Wang, J., Li, Z., He, Y., Pan, F., Chen, S., Rhodes, S., Nguyen, L., Yuan, J., Jiang, L., Yang, X., Weeks, O., Liu, Z., Zhou, J., Ni, H., Cai, C. L., Xu, M., & Yang, F. C. (2014). Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice. Blood, 123(4), 541-553. https://doi.org/10.1182/blood-2013-05-500272