title: Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex.
abstract: 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.
authors.affiliation: 1] Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA [2] Sanford Consortium for Regenerative Medicine, La Jolla, California 92037, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Balasubramani
authors.affiliation: Department of Information and Computer Science, Aalto University School of Science, Aalto FI-00076, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Larjo
authors.affiliation: 1] Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA [2] Sanford Consortium for Regenerative Medicine, La Jolla, California 92037, USA.
authors.forename: Jed A
authors.initials: JA
authors.lastname: Bassein
authors.affiliation: 1] Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA [2] Sanford Consortium for Regenerative Medicine, La Jolla, California 92037, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Chang
authors.affiliation: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Hastie
authors.affiliation: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Togher
authors.affiliation: Department of Information and Computer Science, Aalto University School of Science, Aalto FI-00076, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Lähdesmäki
authors.affiliation: 1] Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA [2] Sanford Consortium for Regenerative Medicine, La Jolla, California 92037, USA [3] Department of Pharmacology, University of California, San Diego, California 92093, USA [4] Moores Cancer Center, University of California, San Diego, California 92093, USA.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000235:genetics; D003398:Craniosynostoses / Q000235:genetics; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
chemical_list: C473949:ASXL1 protein, human; C400134:BAP1 protein, human; D006657:Histones; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase