ASXL1
Polycomb group protein ASXL1 (Additional sex combs-like protein 1) [KIAA0978]
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Hematopoietic stem cells (HSCs) have self-renewal capacity and differentiation potential into all lineages of blood cells throughout the lifetime of an organism. The function of HSCs gradually changes during aging. To date, various stress factors influencing HSC aging have been identified. The increased production of reactive oxygen species and DNA damage responses are causatively attributed to HSC aging. The increased apolarity is a prominent feature of aged HSCs, whereas it is less obvious in young HSCs. The bone marrow (BM) microenvironment niche is a crucial factor for HSC aging. Mesenchymal stem cells show skewed differentiation during aging, which leads to decreased bone formation and increased adipogenesis. The accumulation of adipocytes confers negative effects on hematopoiesis. Loss of sympathetic nerve fibers or adrenoreceptor β3 signaling induces premature HSC and niche aging. Epigenetic regulators such as polycomb group proteins and the sirtuin family of proteins act to prevent premature aging. Targeting these factors, several rejuvenation strategies for aged HSCs have been employed in mice. However, we still do not know whether these strategies can be extrapolated to human HSCs. Aging is frequently accompanied by the development of clonal hematopoiesis, which is called age-related clonal hematopoiesis (ARCH) or clonal hematopoiesis of indeterminate potential (CHIP). Most ARCH/CHIP mutations occur in genes encoding epigenetic regulators including DNMT3A, TET2, and ASXL1, which suggests the relevance of epigenetic drift during the aging process. ARCH/CHIP is a strong risk factor for subsequent hematologic cancer. Notably, it also has an impact on the development of non-malignant disorders such as coronary heart disease. Further studies are warranted to decipher the complete picture of molecular crosstalk that regulates HSC aging.
Keywords
- Age-related clonal hematopoiesis
- Aging
- Clonal hematopoiesis of indeterminate potential
- DNA damage
- Epigenetics
- Hematopoietic stem cell
- Polarity
- Reactive oxygen species
- Senescence
- Stem cell niche
The history of clonal hematopoiesis (CH) research is punctuated by several seminal discoveries that have forged our understanding of cancer development. The clever application of the principle of random X-chromosome inactivation (XCI) in females led to the development of the first test to identify clonal derivation of cells. Initially limited by a low level of informativeness, the applicability of these assays expanded with differential methylation-based assays at highly polymorphic genes such as the human androgen receptor (HUMARA). Twenty years ago, the observation that skewing of XCI ratios increases as women age was the first clue that led to the identification of mutations in the TET2 gene in hematologically normal aging individuals. In 2014, large-scale genomic approaches of three cohorts allowed definition of CH, which was reported to increase the risk of developing hematologic cancers and cardiovascular diseases. These observations created a fertile field of investigation aimed at investigating the etiology and consequences of CH. The most frequently mutated genes in CH are DNMT3A, TET2, and ASXL1, which have a role in hematopoietic stem cell (HSC) development and self-renewal. These mutations confer a competitive advantage to the CH clones. However, the penetrance of CH is age dependent but incomplete, suggesting the influence of extrinsic factors. Recent data attribute a modest role to genetic predisposition, but several observations point to the impact of a pro-inflammatory milieu that advantages the mutated clones. CH may be a barometer of nonhealthy aging, and interventions devised at curbing its initiation or progression should be a research priority.
MeSH Terms
- Adult
- Aging
- Biomedical Research
- Chromosomes, Human, X
- DNA-Binding Proteins
- Female
- Hematopoiesis
- Hematopoietic Stem Cells
- History, 20th Century
- History, 21st Century
- Humans
- Male
- Mutation
- Proto-Oncogene Proteins
- Receptors, Androgen
- Repressor Proteins
- X Chromosome Inactivation
Recent advances in DNA sequencing technologies have enhanced our knowledge about several diseases. Coupled with easy accessibility to blood samples, hematology plays a leading role in understanding the process of carcinogenesis. Clonal hematopoiesis (CH) with somatic mutations is observed in at least 10% of people over 65 years of age, without apparent hematologic disorders. CH is associated with increased risk of hematologic malignancies, which is indicative of a pre-malignant condition. Therefore, a better understanding of CH will help elucidate the mechanism of multi-step tumorigenesis in the hematopoietic system. Somatic mutations of ASXL1 are frequently detected in CH and myeloid malignancies. Although ASXL1 does not have any catalytic activity, it is involved in multiple histone modifications including H3K4me3, H3K27me3, and H2AK119Ub, suggesting its function as a scaffolding protein. Most ASXL1 mutations detected in CH and myeloid malignancies are frameshift or nonsense mutations of the last exon, generating a C-terminally truncated protein. Deletion of Asxl1 or expression of mutant ASXL1 in mice alters histone modifications and facilitates aberrant gene expression, resulting in myeloid transformation. On the contrary, these mice exhibit impaired functioning of hematopoietic stem cells (HSCs), suggesting the negative effects of ASXL1 mutations on stem cell function. Thus, how ASXL1 mutations induce a clonal advantage of hematopoietic cells and subsequent CH development has not been elucidated. Here, we have reviewed the current literature that enhances our understanding of ASXL1, including its mutational landscape, function, and involvement of its mutation in pathogenesis of CH and myeloid malignancies. Finally, we discuss the potential causes of CH harboring ASXL1 mutations with our latest knowledge.
MeSH Terms
- Aged
- Aging
- Animals
- Clonal Evolution
- Codon, Nonsense
- Hematologic Neoplasms
- Hematopoiesis
- Humans
- Myeloproliferative Disorders
- Neoplasm Proteins
- Repressor Proteins
Ageing and inflammation strongly drive the risk of cardiovascular disease. Work over the past decade has uncovered a common condition characterized by the positive selection of certain somatic mutations in haematopoietic stem cells in ageing humans. This phenomenon, known as clonal haematopoiesis of indeterminate potential (CHIP), occurs most commonly as a result of mutations in the transcriptional regulators DNMT3A, TET2 and ASXL1. CHIP is associated with a variety of adverse outcomes, including haematological cancer and death. Surprisingly, CHIP is also associated with a doubling of the risk of atherosclerotic cardiovascular disease. Studies in mice support the causality of this relationship. Mutations in TET2, which are among the most commonly found mutations in CHIP, lead to increased expression of inflammatory genes in innate immune cells, potentially explaining the link between mutations and increased cardiovascular risk. Therapies targeting the mutant clones or the increased inflammatory mediators might be useful for ameliorating the risk of cardiovascular disease. We propose that the mutations leading to clonal haematopoiesis contribute to the increased inflammation seen in ageing and thereby explain some of the age-related risk of cardiovascular disease.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Animals
- Cardiovascular Diseases
- DNA (Cytosine-5-)-Methyltransferases
- DNA-Binding Proteins
- Genetic Predisposition to Disease
- Hematopoiesis
- Hematopoietic Stem Cells
- Humans
- Inflammation
- Middle Aged
- Mutation
- Phenotype
- Proto-Oncogene Proteins
- Repressor Proteins
- Risk Assessment
- Risk Factors
Recent progress in whole genome sequencing has identified recurrent somatic mutations in the additional sex combs like 1 (ASXL1) gene in a variety of hematological disorders and even in premalignant conditions. However, the molecular mechanisms regarding the contribution of ASXL1 mutation to the pathogenesis of premalignant conditions remain largely unelucidated. Thus, we investigated the biological effects of mutant Asxl1 using newly-generated knock-in (KI) mice. Heterozygous mutant KI mice developed phenotypes resembling human low-risk myelodysplastic syndromes (MDS), and some of them developed an MDS/myeloproliferative neoplasm-like disease after a long latency. The H2AK119ub1 level around the promoter region of p16 was significantly decreased in KI hematopoietic stem cells (HSCs), suggesting perturbation of Bmi1-driven H2AK119ub1 histone modification by mutant Asxl1. The mutant Asxl1 failed to interact with Bmi1, although wild type ASXL1 protein did not. When p16 expression was depleted in Asxl1 KI mice, the HSC pool was restored, and apoptosis was ameliorated in HSCs. These findings demonstrate that the loss of protein interaction between mutant Asxl1 and Bmi1 affected the activity of Prc1. The subsequent derepression of p16 by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in heterozygous Asxl1 KI mice.
MeSH Terms
- Animals
- Disease Models, Animal
- Gene Knock-In Techniques
- Hematopoietic Stem Cells
- Histones
- Mice
- Mutation
- Myelodysplastic Syndromes
- Phenotype
- Polycomb Repressive Complex 1
- Proto-Oncogene Proteins
- Repressor Proteins
- Ubiquitination
Keywords
- ASXL1
- CHIP
- Senescence
- p16Ink4a
The clonal hematopoiesis when occurring without hematologic abnormalities is defined as clonal hematopoiesis of indeterminate potential (CHIP). Aging causes accumulation of somatic mutations, and hematopoietic stem cells (HSCs) can develop clonal expansion of different lineages by these mutations. CHIP has a correlation with cancer and cardiovascular disease (CVD) through acquired mutations in genes. DNMT3A, TET2, ASXL1, and JAK2 genes as well as other genes are the most common somatic mutations causing CHIP and CVD in an older age. Other factors such as cholesterol level, laboratory tests and indexes also affect CVD. In addition, mutations in adenosine triphosphate-binding cassette transporters and also chronic stress in nervous system can result in HSCs proliferation and CVD. However, laboratory tests and indexes are not sensitive for CVD diagnosis. But the therapeutic interventions can be helpful to prevent CVD cases by targeting somatic mutations, chemokine receptors, and growth factors in HSCs. Also, new drugs can control CVD by targeting of cells and their signaling pathways in HSCs. Therefore, more investigations are needed and more questions should be answered for the relationship between CHIP and CVD as a challenging issue in future.
MeSH Terms
- Aging
- Cardiovascular Diseases
- Cell Lineage
- Clonal Evolution
- DNA (Cytosine-5-)-Methyltransferases
- DNA-Binding Proteins
- Hematopoiesis
- Hematopoietic Stem Cells
- Humans
- Janus Kinase 2
- Mutation
- Proto-Oncogene Proteins
- Repressor Proteins
Keywords
- cardiovascular disease
- clonal hematopoiesis
- genes
- mechanisms
Epigenetic marks, such as histone modifications or DNA methylation, regulate tissue specific gene expression by affecting the structures and accessibility of chromatin or DNA. Epigenetics, the molecular mechanisms regulating the epigenome, would therefore be critically involved in development and cell differentiation versus proliferation. Histone modifications include methylation, acetylation, phosphorylation and ubiquitination of specific lysine, arginine or serine residues on histone tails, and each modification has its own specific effect on gene expressions. Modification of histones is accomplished by multimeric protein complexes including polycomb and trithorax group proteins. Regulation of DNA methylation is another mechanism of epigenetic regulation, which is achieved by DNA methyltransferase (DNMT) and TET family proteins. Methylation of cysteine residues on DNA generally leads to transcriptional repression, and oxidation of methylated cysteines provides another type of molecular mark on DNA that regulates gene expression. Next generation sequencing of tumor genomes has uncovered recurrent somatic mutations of epigenetic genes such as DNMT3A, TET2, and ASXL1 in hematologic malignancies, showing that epigenetic dysregulation is a critical step leading to the transformation of hematopoietic cells. Rigorous integrated functional analyses of mutated epigenetic genes are currently underway, and are anticipated to lead to the development of novel molecularly targeted therapies for hematologic malignancies.
MeSH Terms
- Aging
- Animals
- DNA Methylation
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Hematologic Neoplasms
- Histones
- Humans
The deubiquitinase (DUB) and tumor suppressor BAP1 catalyzes ubiquitin removal from histone H2A Lys-119 and coordinates cell proliferation, but how BAP1 partners modulate its function remains poorly understood. Here, we report that BAP1 forms two mutually exclusive complexes with the transcriptional regulators ASXL1 and ASXL2, which are necessary for maintaining proper protein levels of this DUB. Conversely, BAP1 is essential for maintaining ASXL2, but not ASXL1, protein stability. Notably, cancer-associated loss of BAP1 expression results in ASXL2 destabilization and hence loss of its function. ASXL1 and ASXL2 use their ASXM domains to interact with the C-terminal domain (CTD) of BAP1, and these interactions are required for ubiquitin binding and H2A deubiquitination. The deubiquitination-promoting effect of ASXM requires intramolecular interactions between catalytic and non-catalytic domains of BAP1, which generate a composite ubiquitin-binding interface (CUBI). Notably, the CUBI engages multiple interactions with ubiquitin involving (i) the ubiquitin carboxyl hydrolase catalytic domain of BAP1, which interacts with the hydrophobic patch of ubiquitin, and (ii) the CTD domain, which interacts with a charged patch of ubiquitin. Significantly, we identified cancer-associated mutations of BAP1 that disrupt the CUBI and notably an in-frame deletion in the CTD that inhibits its interaction with ASXL1/2 and DUB activity and deregulates cell proliferation. Moreover, we demonstrated that BAP1 interaction with ASXL2 regulates cell senescence and that ASXL2 cancer-associated mutations disrupt BAP1 DUB activity. Thus, inactivation of the BAP1/ASXL2 axis might contribute to cancer development.
MeSH Terms
- Cell Proliferation
- HEK293 Cells
- HeLa Cells
- Histones
- Humans
- Multiprotein Complexes
- Neoplasms
- Repressor Proteins
- Tumor Suppressor Proteins
- Ubiquitin Thiolesterase
- Ubiquitin-Specific Proteases
Keywords
- ASXL
- BAP1
- Calypso
- Polycomb Group Proteins
- cancer biology
- cell proliferation
- cellular senescence
- deubiquitylation (deubiquitination)
- epigenetics
- histone H2A ubiquitination