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

TitleLoss of Asxl1 leads to myelodysplastic syndrome-like disease in mice.
Publication TypeJournal Article
Year of Publication2013
AuthorsWang 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
JournalBlood
Date Published2013 Nov 19
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 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.

DOI10.2147/CLEP.S53009
Alternate JournalBlood