title: Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice.
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 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.
authors.affiliation: Department of Pediatrics, and.
authors.forename: Jiapeng
authors.initials: J
authors.lastname: Wang
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Li
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: He
authors.forename: Feng
authors.initials: F
authors.lastname: Pan
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.forename: Steven
authors.initials: S
authors.lastname: Rhodes
authors.forename: Lihn
authors.initials: L
authors.lastname: Nguyen
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Xianlin
authors.initials: X
authors.lastname: Yang
authors.forename: Ophelia
authors.initials: O
authors.lastname: Weeks
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Liu
authors.forename: Jiehao
authors.initials: J
authors.lastname: Zhou
authors.forename: Hongyu
authors.initials: H
authors.lastname: Ni
authors.forename: Chen-Leng
authors.initials: CL
authors.lastname: Cai
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D017353:Gene Deletion; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006706:Homeostasis; D006720:Homozygote; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology*
chemical_list: C510915:Asxl1 protein, mouse; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins