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PMID:19861679
| Citation |
Fisher, CL, Pineault, N, Brookes, C, Helgason, CD, Ohta, H, Bodner, C, Hess, JL, Humphries, RK and Brock, HW (2010) Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. Blood 115:38-46 |
|---|---|
| Abstract |
The Additional sex combs like 1 (Asxl1) gene is 1 of 3 mammalian homologs of the Additional sex combs (Asx) gene of Drosophila. Asx is unusual because it is required to maintain both activation and silencing of Hox genes in flies and mice. Asxl proteins are characterized by an amino terminal homology domain, by interaction domains for nuclear receptors, and by a C-terminal plant homeodomain protein-protein interaction domain. A recent study of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) revealed a high incidence of truncation mutations that would delete the PHD domain of ASXL1. Here, we show that Asxl1 is expressed in all hematopoietic cell fractions analyzed. Asxl1 knockout mice exhibit defects in frequency of differentiation of lymphoid and myeloid progenitors, but not in multipotent progenitors. We do not detect effects on hematopoietic stem cells, or in peripheral blood. Notably, we do not detect severe myelodysplastic phenotypes or leukemia in this loss-of-function model. We conclude that Asxl1 is needed for normal hematopoiesis. The mild phenotypes observed may be because other Asxl genes have redundant function with Asxl1, or alternatively, MDS or oncogenic phenotypes may result from gain-of-function Asxl mutations caused by genomic amplification, gene fusion, or truncation of Asxl1. |
| Links |
PubMed PMC2803690 Online version:10.1182/blood-2009-07-230698 |
| Keywords |
Animals; B-Lymphocytes/cytology; B-Lymphocytes/metabolism; Cell Count; Cell Lineage; Cells, Cultured; Flow Cytometry; Gene Targeting; Hematopoiesis/genetics; Hematopoietic Stem Cells/metabolism; Leukemia/genetics; Mice; Mice, Mutant Strains; Mutation/genetics; Myelodysplastic Syndromes/genetics; Myeloid Cells/pathology; Repressor Proteins/genetics; Splenomegaly/pathology; T-Lymphocytes/cytology; T-Lymphocytes/metabolism; Thymus Gland/cytology |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
|
MOUSE:A0A0A6YW14 |
located_in |
GO:0009897: external side of plasma membrane |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | ||
|
MOUSE:A0A0A6YXD7 |
located_in |
GO:0009897: external side of plasma membrane |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | ||
|
MOUSE:IGHM |
located_in |
GO:0009897: external side of plasma membrane |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | ||
|
MOUSE:PTPRC |
located_in |
GO:0009897: external side of plasma membrane |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | ||
|
involved_in |
GO:0048534: hematopoietic or lymphoid organ development |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
involved_in |
GO:0048538: thymus development |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
involved_in |
GO:0048539: bone marrow development |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
involved_in |
GO:0048872: homeostasis of number of cells |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
involved_in |
GO:0009887: animal organ morphogenesis |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
involved_in |
GO:0030097: hemopoiesis |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
involved_in |
GO:0000902: cell morphogenesis |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
acts_upstream_of_or_within |
GO:0000902: cell morphogenesis |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
acts_upstream_of_or_within |
GO:0009887: animal organ morphogenesis |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
acts_upstream_of_or_within |
GO:0048534: hematopoietic or lymphoid organ development |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
acts_upstream_of_or_within |
GO:0048539: bone marrow development |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
acts_upstream_of_or_within |
GO:0030097: hemopoiesis |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
acts_upstream_of_or_within |
GO:0048538: thymus development |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
|
acts_upstream_of_or_within |
GO:0048872: homeostasis of number of cells |
ECO:0000315: mutant phenotype evidence used in manual assertion |
MGI:MGI:4418244 |
P |
Seeded From UniProt |
complete | ||
Notes
See also
References
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