Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1–BAP1 complex

ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring–Opitz syndrome. Here we demonstrate that ASXL1 truncations confer enhanced activity...

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Bibliographic Details
Published in:	Nature communications Vol. 6; no. 1; p. 7307
Main Authors:	Balasubramani, Anand, Larjo, Antti, Bassein, Jed A., Chang, Xing, Hastie, Ryan B., Togher, Susan M., Lähdesmäki, Harri, Rao, Anjana
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 22-06-2015 Nature Publishing Group Nature Pub. Group
Subjects:	13/31 38/15 38/91 42/100 631/337/474/2073 64/60 692/699/67/68 96/109 Animals Bone Marrow Cells Cell Differentiation - genetics Craniosynostoses - genetics HEK293 Cells Hematopoietic Stem Cells - cytology Hematopoietic Stem Cells - metabolism Histones - metabolism Humanities and Social Sciences Humans Intellectual Disability - genetics Leukemia, Myeloid - genetics Mast Cells - cytology Mast Cells - metabolism Mice Mice, Inbred C57BL multidisciplinary Mutation Promoter Regions, Genetic Repressor Proteins - genetics Repressor Proteins - metabolism Science Science (multidisciplinary) Tumor Suppressor Proteins - metabolism Ubiquitin Thiolesterase - metabolism
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Summary:	ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring–Opitz syndrome. Here we demonstrate that ASXL1 truncations confer enhanced activity on the ASXL1–BAP1 complex. Stable expression of truncated, hyperactive ASXL1–BAP1 complexes in a haematopoietic precursor cell line results in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters are marked by both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes require the catalytic activity of BAP1, indicating that they are downstream consequences of H2AK119Ub erasure. In bone marrow precursors, expression of truncated ASXL1–BAP1 complex cooperates with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo . Our data raise the possibility that ASXL1 truncation mutations confer gain-of-function on the ASXL–BAP1 complex. Premature truncations of ASXL1, a subunit of a deubiquitinase complex, are frequent in myeloid leukemia. Here, the authors show that expression of truncated ASXL1 in a haematopoietic precursor cell line enhances the deubiquitinase activity and leads to differentiation to the mast cell lineage.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms8307