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Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice.
|Title||Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||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|
|Date Published||2013 Nov 19|
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 MDS, including dysplastic neutrophils and multiple lineage cytopenia. Asxl1(-/-) mice had a reduced HSC-pool and Asxl1(-/-) HSCs exhibited decreased hematopoietic repopulating capacity with skewed cell differentiation favoring granulocytic lineage. Importantly, Asxl1(+/-) mice also developed mild MDS-like disease, which could progress to MDS/MPN, demonstrating a haploinsufficient effect of Asxl1 in the pathogenesis of myeloid malignancies. Asxl1-loss led to an increased apoptosis and mitosis in LK cells, consistent with human MDS. Furthermore, Asxl1(-/-) LK cells exhibited decreased global levels of H3K27me3 and H3K4me3, and altered expression of genes regulating apoptosis (Bcl2, Bcl2l12 and Bcl2l13). Collectively, we report a novel ASXL1 murine model which 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.