Loss-of-function additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia

Cynthia L. Fisher, Nicolas Pineault, Christy Brookes, Cheryl D. Helgason, Hideaki Ohta, Caroline Bodner, Jay Hess, R. Keith Humphries, Hugh W. Brock

Research output: Contribution to journalArticle

108 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)38-46
Number of pages9
JournalBlood
Volume115
Issue number1
DOIs
StatePublished - Jan 7 2010
Externally publishedYes

Fingerprint

Comb and Wattles
Hematopoiesis
Leukemia
Genes
Mutation
Protein Interaction Domains and Motifs
Homeodomain Proteins
Myelodysplastic Syndromes
Cytoplasmic and Nuclear Receptors
Stem cells
Phenotype
Blood
Fusion reactions
Chemical activation
Leukemia, Myelomonocytic, Chronic
Plant Proteins
Defects
Homeobox Genes
Gene Fusion
Hematopoietic Stem Cells

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Fisher, C. L., Pineault, N., Brookes, C., Helgason, C. D., Ohta, H., Bodner, C., ... Brock, H. W. (2010). Loss-of-function additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. Blood, 115(1), 38-46. https://doi.org/10.1182/blood-2009-07-230698

Loss-of-function additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. / Fisher, Cynthia L.; Pineault, Nicolas; Brookes, Christy; Helgason, Cheryl D.; Ohta, Hideaki; Bodner, Caroline; Hess, Jay; Humphries, R. Keith; Brock, Hugh W.

In: Blood, Vol. 115, No. 1, 07.01.2010, p. 38-46.

Research output: Contribution to journalArticle

Fisher, CL, Pineault, N, Brookes, C, Helgason, CD, Ohta, H, Bodner, C, Hess, J, Humphries, RK & Brock, HW 2010, 'Loss-of-function additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia', Blood, vol. 115, no. 1, pp. 38-46. https://doi.org/10.1182/blood-2009-07-230698
Fisher, Cynthia L. ; Pineault, Nicolas ; Brookes, Christy ; Helgason, Cheryl D. ; Ohta, Hideaki ; Bodner, Caroline ; Hess, Jay ; Humphries, R. Keith ; Brock, Hugh W. / Loss-of-function additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. In: Blood. 2010 ; Vol. 115, No. 1. pp. 38-46.
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