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PMID:19861679

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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

MOUSE:ASXL1

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

MOUSE:ASXL1

involved_in

GO:0048538: thymus development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4418244

P

Seeded From UniProt

complete

MOUSE:ASXL1

involved_in

GO:0048539: bone marrow development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4418244

P

Seeded From UniProt

complete

MOUSE:ASXL1

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

MOUSE:ASXL1

involved_in

GO:0009887: animal organ morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4418244

P

Seeded From UniProt

complete

MOUSE:ASXL1

involved_in

GO:0030097: hemopoiesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4418244

P

Seeded From UniProt

complete

MOUSE:ASXL1

involved_in

GO:0000902: cell morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4418244

P

Seeded From UniProt

complete

MOUSE:ASXL1

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

MOUSE:ASXL1

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

MOUSE:ASXL1

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

MOUSE:ASXL1

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

MOUSE:ASXL1

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

MOUSE:ASXL1

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

MOUSE:ASXL1

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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