PLoS Genet. In Drosophila, ASX forms a complex with the ubiquitin carboxy-terminal hydrolase calypso to constitute the recently identified polycomb repressive deubiquitinase (PR-DUB) complex [3, 6]. A recent study of 476 cases with intermediate-risk de novo AML showed that ASXL1 mutations have a major impact on outcome [51]. Bejar R, Stevenson K, Abdel-Wahab O, Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, Kantarjian H, Raza A, Levine RL, Neuberg D, Ebert BL: Clinical effect of point mutations in myelodysplastic syndromes. A composite score was then determined using phenotypic variables as defined by CPSS and the “Genetic Risk Group”. http://creativecommons.org/licenses/by/2.0. The calypso/BAP1 DUB deubiquitylates K119ub on histone H2A, leading to gene repression. PubMed Google Scholar. All authors have contributed ideas, discussions, and have participated in the writing of the manuscript. 2019 May 7;12(5):dmm035790. Blood. 114. This article is published under license to BioMed Central Ltd. J Biol Chem. doi: 10.1242/dmm.035790. FOIA In MDSs, ASXL1 mutations are more frequent in refractory anemia with excess of blasts (RAEB) than in the other forms such as refractory anemia with ring sideroblasts (RARS) [1, 5, 22]. In almost all studies, and whatever the type of myeloid malignancy, ASXL1 mutations are associated with adverse features including, but not limited to myelodysplasia, myelofibrosis or progression to AML. ASXL1 (20–70%), SETBP1 (25–30%) and TET2 (43%) mutations are the most common mutations detected in aCML [ 66, 67 ]. ASXL1 mutations are found in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). 2,13,14 In CMML, these mutations have been incorporated into three molecularly integrated prognostic models: Mayo Molecular Model, CPSS-molecular, and the Groupe Francophone des Myelodysplasies model. One study has described this mutation as a PCR artefact [19], but because it is not found in germ-line DNAs, control DNAs or other studied types of cancers such as breast cancer, it is now generally considered to be a bona fide mutation. Boultwood J, Perry J, Pellagatti A, Fernandez-Mercado M, Fernandez-Santamaria C, Calasanz MJ, Larrayoz MJ, Garcia-Delgado M, Giagounidis A, Malcovati L, Della Porta MG, Jädersten M, Killick S, Hellström-Lindberg E, Cazzola M, Wainscoat JS: Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia. Epub 2011 Sep 9. 2012, 11 (1): 119-131. doi:10.3324. ASXL1 mutations can also cooperate with mutations in genes encoding signaling (CBL, JAK2, NF1, RAS) and splicing proteins (SF3B1, SRSF2, U2AF35). Nature. J Clin Oncol. Below reported mutations (see Table 1) are shown along the protein: circles and triangles indicate frameshift and nonsense mutations, respectively, and the colors correspond to the exon location. Conserved domains of mammalian Asxl…, Figure 3. Prevention and treatment information (HHS). Coupled with the standardized international prognostic scoring system (IPSS), mutations in these five genes could help refine the prognosis evaluation of MDSs. of multiple mutations including ASXL1, NRAS, RUNX1 and SETBP1. 2006, 281: 17588-17598. 2011, 44: 47-52. Int J Oncol. Mutations of ASXL1 have been identified in a variety of myeloid neoplasms, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia or MDS-MPN, and chronic myeloid leukemia, and are uniformly associated with poor prognosis. Since the discovery of activating mutations in JAK2 in patients with myeloproliferative neoplasms (MPNs) in 2005, gene discovery efforts have identified additional disease alleles, which can predate or occur subsequent to acquisition of JAK2/MPL mutations. In a series of secondary AML with multilineage dysplasia we found that in cases resulting from a transformation of a known MDS the same ASXL1 mutation was present at both the chronic and acute stages (Devillier et al., submitted). These observations suggest that ASXL1 mutations may constitute early hits in leukemogenesis and precede other alterations such as JAK2 and TET2 mutations [24, 25, 28]. Leukemia. ASXL1 is mutated in all types of malignant myeloid diseases, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). Leuk Res. 2011, 364: 2496-2506. Abdel-Wahab O, Manshouri T, Patel J, Harris K, Yao J, Hedvat C, Heguy A, Bueso-Ramos C, Kantarjian H, Levine RL, Verstovsek S. Cancer Res. This site needs JavaScript to work properly. The functional relevance of some reported missense mutations is not clear. Few deletions of the gene have been reported and ASXL1 is generally not included in the more telomeric 20q13 deletion that is often observed in myeloid diseases. 10.1038/nature08448. Gelsi-Boyer V, Trouplin V, Adelaide J, Bonansea J, Cervera N, Carbuccia N, Lagarde A, Prebet T, Nezri M, Sainty D, Olschwang S, Xerri L, Chaffanet M, Mozziconacci MJ, Vey N, Birnbaum D: Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Lee JM, Lee H, Eom KS, Lee SE, Kim M, Kim Y. J Clin Med. 2009, 4: e4750-10.1371/journal.pone.0004750. The ASXL1 protein belongs to protein complexes involved … Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, Wilm M, Muir TW, Müller J: Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Abdel-Wahab O, Pardanani A, Patel J, Wadleigh M, Lasho T, Heguy A, Beran M, Gilliland DG, Levine RL, Tefferi A: Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms. The authors declare that they have no competing interests. Unable to load your collection due to an error, Unable to load your delegates due to an error. ASXL1: 14.0%; Mutations in DTA genes were observed in: 62.5% of patients with PV; 12% of patients with ET; 56.3% of patients with primary MF; 45.5% of patients with secondary MF; When looking at all MPN patients as a whole, no association between DTA mutations and thrombosis was observed Et ~ 1%. Molecular aspects of myeloproliferative neoplasms. Would you like email updates of new search results? 2010, 24: 469-473. PV ~ 2%. Curr Opin Hematol. 2 It has been reported that knockdown or deletion of ASXL1 induces MDS-like … Copyright © 2012 Elsevier Inc. All rights reserved. The vast majority of the ASXL1 mutations found in myeloid malignancies affect the twelfth exon of the gene although rare mutations in other exons have been detected [18]. 2010, 70: 447-452. For example, the prognostic importance of mutations in TET2 and ASXL1 in MPN patients is not clear. 2010, 24: 1656-1657. However, there is also evidence to suggest that the opposite is true in some cases. 2012. 2012, 119: 1208-1213. ASXL3 expression and functions remain to be determined [17]. 2020 Jul 14;41(7):576-582. doi: 10.3760/cma.j.issn.0253-2727.2020.07.008. 2010, 150: 83-87. 2011, 118: 5227-5234. With the exception of NPM1 and FLT3, it seems that ASXL1 mutations coincide with mutations in many known genes including EZH2[18], IDH1/2, RUNX1 and TET2[21, 22]. Recent data have shown that ASXL1 interacts with components of the polycomb complex PRC2, namely EZH2 and SUZ12, two proteins involved in the deposition of H3K27me3 histone repressive marks. Blood. 2010 Mar;91(2):165-73. doi: 10.1007/s12185-010-0530-z. Br J Haematol. 2011 Mar;18(2):117-23. doi: 10.1097/MOH.0b013e328343998e. Differences in terms of overall survival were found only in AML-MRC patients without prior MDS or MDS/MPN and with intermediate-risk karyotype, having ASXL1+ patients a worst outcome than ASXL1-. Four risk categories Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. 2009, 23: 2183-2186. Inhibition of ASXL1 function leads to loss of H3K27me3 histone marks. JAK2 phosphorylates histone H3 and excludes HP1α from chromatin [13]. 2q33.3/ 15q26.1. HP1α binds to histone H3. Carbuccia N, Trouplin V, Gelsi-Boyer V, Murati A, Rocquain J, Adélaïde J, Olschwang S, Xerri L, Vey N, Chaffanet M, Birnbaum D, Mozziconacci MJ: Mutual exclusion of ASXL1 and NPM1 mutations in a series of acute myeloid leukemias. 10.1182/blood-2011-08-368225. Park UH, Yoon SK, Park T, Kim EJ, Um SJ: Additional sex comb-like (ASXL) proteins 1 and 2 play opposite roles in adipogenesis via reciprocal regulation of peroxisome proliferator-activated receptor {gamma}. 10.3324/haematol.2011.045591. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy Yes, I accept cookies An Q, Wright SL, Moorman AV, Parker H, Griffiths M, Ross FM, Davies T, Harrison CJ, Strefford JC: Heterogeneous breakpoints in patients with acute lymphoblastic leukemia and the dic(9;20)(p11-13;q11) show recurrent involvement of genes at 20q11.21. Of note, IDH1/2 mutations are commonly identified in secondary gliomas that arise from a preceding lower-grade astrocytoma,( 14 ) suggesting IDH1/2 mutations contribute to progression to high-grade glioblastoma. Blood. Tan YX, Xu N, Huang JX, Wu WE, Liu L, Zhou LL, Liu XL, Yin CX, Xu D, Zhou X. Zhonghua Xue Ye Xue Za Zhi. Role of TET2 in DNA hydroxymethylation and DNA demethylation, Figure 2. ASXL1 regulates epigenetic marks and transcription through interaction with polycomb complex proteins and various transcription activators and repressors [3–5]. No … This domain has been referred to as a HARE-HTH domain (. Both driver and sub-clonal mutations are now taken into consideration in new prognostic scoring systems and may be better investigated using next generation sequence (NGS) technology. Both MYST3 and EPC1 are epigenetic regulators and these fusion proteins probably disrupt epigenetic protein complexes. Session: 611. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. ASXL1 mutations are universally detrimental across myeloid neoplasms and have a particularly poor outlook in CMML. 2010, 42: 665-667. 2011, 29: 392-397. 2012, 97: 388-392. 2011, 118: 6920-6929. 2010, 151: 365-375. 10.1111/j.1365-2141.2009.07697.x. Like TET2 mutations, ASXL1 mutations are found in chronic and acute stages of myeloid malignancies. Google Scholar. statement and The specific mechanisms by which ASXL1 mutations affect the development of MDS are not clear. 10.1038/ng.868. 2009, 48: 768-776. 10.1158/1078-0432.CCR-09-2112. [Analysis of gene mutations and clinic features in 108 patients with myeloproliferative neoplasm]. 2012, 156: 404-407. 10.1002/gcc.10172. Dohner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD: Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet.