The Role of Additional Sex Combs-Like Proteins in Cancer

Micol, Jean-Baptiste; Abdel‐Wahab, Omar

doi:10.1101/cshperspect.a026526

Cited by 57 publications

(60 citation statements)

References 78 publications

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“…With the exception of one report indicating that an evolutionarily conserved retrotransposon modulates ASXL3 expression during neural development by encoding an alternatively spliced exon leading to nonsense mediated decay of the transcript (45), there are no published data pertaining to mechanisms regulating ASXL3 expression in normal cells. Furthermore, whereas truncating mutations of ASXL3 have been associated with autism and Bainbridge-Ropers syndrome (46), as well as a low percentage of melanomas (29, 47), there are no published data regarding mechanisms and clinical implications of ASXL3 over-expression in cancers. ASXL3 is located on 18q11, in a region not previously associated with genomic abnormalities by cytogenetic analysis in SCLC (48).…”

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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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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“…Another common CHIP mutation in epigenetic regulator genes is ASXL1 gene, encoding additional sex combs like 1 protein which in uences histone modi cations and gene expression (38). Mutation in ASXL1 gene can result in inhibition of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation.…”

Section: Discussionmentioning

confidence: 99%

Elevated expression of clonal hematopoiesis of indeterminate potential in patients with coronary endothelial dysfunction is associated with future cardiovascular events

Ganji¹,

Lasho²,

Toya³

et al. 2020

Preprint

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Aims We aimed to test the hypothesis that the presence of clonal hematopoiesis of indeterminate potential (CHIP) in peripheral blood cells is associated with coronary endothelial dysfunction, enhanced inflammatory markers, and major adverse cardiovascular events (MACE).Methods and results We compared targeted next generation sequencing (35 CHIP related genes) between patients with coronary endothelial dysfunction (n = 123) and controls (n=65). Coronary endothelial dysfunction was defined by ≥ 20% decrease in coronary artery diameter (CAD) or ≤ 50% increase in coronary blood flow (CBF) in response to acetylcholine injection compared to baseline. Plasma cytokine levels of Interleukin (IL)-6 and IL-8 were also assessed. Patients were subsequently followed for 12.2 ± 4.3 years. Clonal hematopoiesis relevant gene mutations were found in 1 individual in normal endothelial function group (1.5%) and 11 cases in endothelial dysfunction group (9.3%) (p = 0.04). Additionally, CHIP mutations were associated with an increased risk of MACE (OR = 4.08, P = 0.04). Mutations in ASXL1, DNMT3A and TET2 in the endothelial dysfunction group were also associated with increased levels of IL-6 and IL-8 (P = 0.001, P = 0.003; respectively).Conclusion The current study demonstrates a high frequency of CHIP in patients with coronary endothelial dysfunction as well as an association between mutations in three most common epigenetic regulator genes and increased levels of IL-6 and IL-8. Therefore it infers a probable relationship between CHIP, endothelial dysfunction and cardiovascular adverse events.

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“…In myeloid neoplasms, most of the ASXL1 mutations are somatic ones, whereas germline mutations of ASXL1 are identified in patients with Bohring-Opitz syndrome, a developmental disorder [34]. Although ASXL2 mutations are frequently found in RUNX1-ETO fusion leukemia [35,36], the frequency of ASXL2 mutations in other hematological neoplasms is much lower than that of ASXL1 mutations [37,38]. Unlike ASXL1 Fig.…”

Section: The Structure Of Asxl Family Proteinsmentioning

confidence: 99%

Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms

Asada

Kitamura

2018

Int J Hematol

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An epigenetic modulator Additional sex combs-like 1 (ASXL1) is recurrently mutated in myeloid neoplasms such as myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs). ASXL1 mutations are also frequently detected in clonal hematopoiesis with indeterminate potential (CHIP), which is the clonal expansion of premalignant hematopoietic cells without any evidence of hematological malignancies. Thus, understanding the roles of ASXL1 in hematopoiesis and myeloid neoplasms is a clinically crucial issue. ASXL1 mutations in hematological neoplasms are typically frameshift or nonsense mutations and occur near the 5′ end of the last exon, thereby the transcripts would escape from nonsense-mediated decay, Indeed, we identified the C-terminally truncated mutant protein of ASXL1 in several cell lines derived from patients with myeloid leukemia. In mouse models, expression of the mutant ASXL1 results in impaired hematopoiesis and promotes development of myeloid neoplasms. In addition, recent findings from biochemical analysis have demonstrated that the mutant ASXL1 protein gains new functions including enhancing catalytic activity of BRCA1-associated protein 1 (BAP1), resulting in reduction of H2AK119ub and aberrant gene expression essential for myeloid transformation. In this review, we will focus on the pivotal roles of the mutant ASXL1 on histone modifications and myeloid transformation.

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The Role of Additional Sex Combs-Like Proteins in Cancer

Cited by 57 publications

References 78 publications

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

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

Elevated expression of clonal hematopoiesis of indeterminate potential in patients with coronary endothelial dysfunction is associated with future cardiovascular events

Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms

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