Wang, JiapengLi, ZhaominHe, YongzhengPan, FengChen, ShiRhodes, StevenNguyen, LihnYuan, JinJiang, LiYang, XianlinWeeks, OpheliaLiu, ZiyueZhou, JiehaoNi, HongyuCai, Chen-LengXu, MingjiangYang, Feng-Chun2016-05-112016-05-112014-01-23Wang, J., Li, Z., He, Y., Pan, F., Chen, S., Rhodes, S., … Yang, F.-C. (2014). Loss of Asxl1 leads to myelodysplastic syndrome–like disease in mice. Blood, 123(4), 541–553. http://doi.org/10.1182/blood-2013-05-5002721528-0020https://hdl.handle.net/1805/9566ASXL1 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 and mitosis in Lineage(-)c-Kit(+) (Lin(-)c-Kit(+)) cells, consistent with human MDS. 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 Asxl1(-/-) mice.en-USPublisher PolicyMutationMyelodysplastic SyndromesGeneticsRepressor ProteinsphysiologyArticle