The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer

Daou, Salima; Hammond-Martel, Ian; Mashtalir, Nazar; Barbour, Haithem; Gagnon, Jessica K.; Iannantuono, Nicholas V G; Nkwe, Nadine Sen; Motorina, Alena; Pak, HuiSong; Yu, Helen; Würtele, Hugo; Milot, Éric; Mallette, Frédérick A.; Carbone, Michele; Affar, El Bachir

doi:10.1074/jbc.m115.661553

Cited by 104 publications

(131 citation statements)

References 66 publications

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“…EZH2 is the catalytic component of Polycomb Repressive Complex 2 (PRC2) and serves as a H3K27 methyltransferase activity. ASXL1 and ASXL2 are part of the Polycomb repressive deubiquitinase complex, which removes an ubiquitin from H2AK119 marks, 42 but studies have shown that ASXL proteins may also function in recruitment and/or stabilization of the PRC2 complex to specific loci.…”

Section: Discussionmentioning

confidence: 99%

“…34 The 4 subunits form a ring structure that regulates chromosome segregation during meiosis and mitosis, but recent data suggest additional functions such as double-stranded DNA repair and regulation of transcription. 42,45 In a previous study by Thol et al, recurrent cohesin mutations have been reported in about 6% of AML patients. 45 However, cohesin mutations concerned less than 2% of CBF AML in this study.…”

mentioning

confidence: 92%

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Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Duployez

Marceau-Renaut

Boissel

et al. 2016

Blood

195

186

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Key Points• Recurrent mutations in chromatin modifiers and cohesin were observed in t(8;21) AML, but not inv (16 . Mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML. In contrast, mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies in t(8;21) AML (42% and 18%, respectively), whereas they were nearly absent in inv(16) AML. High KIT mutant allele ratios defined a group of t(8;21) AML patients with poor prognosis, whereas high N/KRAS mutant allele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome. In addition, mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis in patients with tyrosine kinase pathway mutations, suggesting synergic cooperation between these events. These data suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21) vs inv(16) AML.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 92%

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Duployez

Marceau-Renaut

Boissel

et al. 2016

Blood

195

186

View full text Add to dashboard Cite

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“…ASXL proteins also interact with BRCA-1 Associated Protein-1 (BAP1), a ubiquitin hydrolase that mediates de-ubiquitination of H2AK119Ub, the repressive mark placed by the “maintenance” PRC1 (43). BAP1 does not interact with PRC2 proteins (29).…”

Section: Discussionmentioning

confidence: 99%

ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer

et al. 2017

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In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSC (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAEC. Of particular novelty, we identified the PRC2-associated protein, ASXL3 which was markedly upregulated in Lu-iPSC and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity and teratoma formation by Lu-iPSC, and diminished clonogenicity and malignant growth of SCLC cells in-vivo. Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis, and highlight ASXL3 as a novel candidate target for SCLC therapy.

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“…Although both ASXL1 and ASXL2 have been identified to bind to BAP1, recent biochemical characterization of BAP1 complexes by Daou et al (2015) suggest that BAP1 forms two mutually exclusive complexes with ASXL1 and ASXL2. In this study, BAP1 was identified to stabilize ASXL2 via deubiquitination of ASXL2.…”

Section: Effect Of Asxl Mutations On Asxl Functionmentioning

confidence: 99%

The Role of Additional Sex Combs-Like Proteins in Cancer

Micol

Abdel‐Wahab

2016

Cold Spring Harb Perspect Med

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Additional sex combs-like (ASXL) proteins are mammalian homologs of Addition of sex combs (Asx), a protein that regulates the balance of trithorax and Polycomb function in Drosophila. All three ASXL family members (ASXL1, ASXL2, and ASXL3) are affected by somatic or de novo germline mutations in cancer or rare developmental syndromes, respectively. Although Asx is characterized as a catalytic partner for the deubiquitinase Calypso (or BAP1), there are domains of ASXL proteins that are distinct from Asx and the roles and redundancies of ASXL members are not yet well understood. Moreover, it is not yet fully clarified if commonly encountered ASXL1 mutations result in a loss of protein or stable expression of a truncated protein with dominant-negative or gain-of-function properties. This review summarizes our current knowledge of the biological and functional roles of ASXL members in development, cancer, and transcription.

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The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer

Cited by 104 publications

References 66 publications

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer

The Role of Additional Sex Combs-Like Proteins in Cancer

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