The distinct biological implications of Asxl1 mutation and its roles in leukemogenesis revealed by a knock-in mouse model

Hsu, Yueh-Chwen; Chiu, Yu‐Chiao; Lin, Chien‐Chin; Kuo, Yueh‐Hsiung; Hou, Hsin‐An; Tzeng, Yi-Shiuan; Kao, Chein-Jun; Chuang, Po-Han; Tseng, Mei‐Hsuan; Hsiao, Tzu‐Hung; Chou, Wen‐Chien; Tien, Hwei‐Fang

doi:10.1186/s13045-017-0508-x

Cited by 40 publications

(33 citation statements)

References 48 publications

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“…Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases (Gelsi-Boyer et al, 2012;Micol and Abdel-Wahab, 2016), and nearly all ASXL1 mutations lead to the production of C-terminally truncated mutant ASXL1 proteins. To study the oncogenic roles of C-terminally truncated ASXL1, previous studies have employed either transgenic expression (Inoue et al, 2013;Yang et al, 2018) or knock-in mouse models (Hsu et al, 2017;Nagase et al 2018). It has to be noted that transgenic expression is an overexpression system, and knock-in mouse models investigate the effect of Asxl1 mutation in the absence of other collaborative leukemic mutations.…”

Section: Discussionmentioning

confidence: 99%

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

et al. 2020

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Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,

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Section: Discussionmentioning

confidence: 99%

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

et al. 2020

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“…It was already detected as a component of the PR-DUB complex, related to the deubiquitination of histone H2A [89]. Mice models carrying ASXL1 mutation showed myeloid dysplasia and shorter survival, mainly due to PRC2 inactivation [90]. Mutations in the ASXL1 gene have been described in many subtypes of myeloid malignancies and are associated with adverse prognosis, shorter OS and higher risk of progression [88,91].…”

Section: Asxl1 Mutationsmentioning

confidence: 99%

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Panuzzo

Signorino

Calabrese

et al. 2020

JCM

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Acute myeloid leukemia is mainly characterized by a complex and dynamic genomic instability. Next-generation sequencing has significantly improved the ability of diagnostic research to molecularly characterize and stratify patients. This detailed outcome allowed the discovery of new therapeutic targets and predictive biomarkers, which led to develop novel compounds (e.g., IDH 1 and 2 inhibitors), nowadays commonly used for the treatment of adult relapsed or refractory AML. In this review we summarize the most relevant mutations affecting tumor suppressor genes that contribute to the onset and progression of AML pathology. Epigenetic modifications (TET2, IDH1 and IDH2, DNMT3A, ASXL1, WT1, EZH2), DNA repair dysregulation (TP53, NPM1), cell cycle inhibition and deficiency in differentiation (NPM1, CEBPA, TP53 and GATA2) as a consequence of somatic mutations come out as key elements in acute myeloid leukemia and may contribute to relapse and resistance to therapies. Moreover, spliceosomal machinery mutations identified in the last years, even if in a small cohort of acute myeloid leukemia patients, suggested a new opportunity to exploit therapeutically. Targeting these cellular markers will be the main challenge in the near future in an attempt to eradicate leukemia stem cells.

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“…ASXL1 forms a complex with the deubiquitination enzyme BAP1 and removes monoubiquitin from H2AK119Ub, to derepress genes targeted by PRC1 [ 91 ]. Recent studies using mice expressing an ASXL1 mutant demonstrated that an ASXL1 mutation alone is not sufficient for inducing the development of hematologic malignancies [ 92 – 94 ]. However, an ASXL1 mutation increased the susceptibility to leukemogenesis in concert with a RUNX1 mutant or in viral insertional mutagenesis, indicating that mice expressing an ASXL1 mutant represent a premalignant condition like ARCH/CHIP [ 93 ].…”

Section: Main Textmentioning

confidence: 99%

Aging and leukemic evolution of hematopoietic stem cells under various stress conditions

Kurosawa

Iwama

2020

Inflamm Regener

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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.

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The distinct biological implications of Asxl1 mutation and its roles in leukemogenesis revealed by a knock-in mouse model

Cited by 40 publications

References 48 publications

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Aging and leukemic evolution of hematopoietic stem cells under various stress conditions

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