ASXL1

Primary Author(s)*

Kay Weng Choy, MBBS, Monash Medical Centre

Synonyms

ASXL Transcriptional Regulator 1, Additional Sex Combs Like Transcriptional Regulator 1, Additional Sex Combs-Like 1 (Drosophila), KIAA0978, BOPS, MDS

Genomic Location

Cytoband: 20q11.21

Genomic Coordinates:

chr20:32,358,330-32,439,319 (GRCh38/hg38)

chr20:30,946,147-31,027,122 (GRCh37/hg19)

Cancer Category/Type

Haematological malignancies, particularly myeloid neoplasms, e.g., chronic myelomonocytic leukemia, acute myeloid leukemia

Colorectal cancer

Gene Overview

ASXL1 is essential for the activation and repression of homeotic loci (genes that regulate the development of anatomical structures) [1]. It interacts with polycomb and super sex combs (proteins involved in epigenetic regulation of chromatin) [1]. Given the location of ASXL1 in the chromosome band 20q11, the association of this chromosome region with amplification in tumors and the increasing evidence for the involvement of chromatin proteins in cancer, expression of ASXL1 in a variety of cell lines derived from human tumors has been examined closely [1,2]. It is expressed at higher levels in several cancer cell lines such as in myeloid neoplasms and colorectal cancer [1,3].

ASXL1 contains an N-terminal ASX homology domain, ASXH, and a C-terminal plant homeodomain, PHD [4]. The gene encodes a member of the polycomb family of the chromatic binding proteins and is involved in epigenetic regulation of gene expression via its PHD finger (figure 1) [1]. The PHD finger interacts with the polycomb group repressive complex protein (PRC1 and PRC2) and other transcription activators and repressors to regulate chromatin [1].

ASXL1 mutations in myeloid neoplasms are associated with a truncation in exon 12 (NM_015338.5), adjacent to the PHD finger [5,6]. In vitro studies in leukemic cells demonstrate that there is a loss of ASXL1 protein expression when ASXL1 mutations are seen in myeloid neoplasms [7]. The most common ASXL1 mutation associated with myeloid neoplasms is c.1934_1935insG (NM_015338.5) (p.G646Wfs*12), reportedly accounting for more than 50% of cases [1]. It is suggested that the mutation is responsible for a truncated ASXL1 protein that lacks the PHD finger, rather than the loss of the entire ASXL1 protein [1].

AXSL1 mutations in myeloid neoplasms

ASXL1 mutations have been found in almost all types of myeloid malignancies, including MDS, AML and MPN [1].

ASXL1 mutations are more likely to be seen in secondary AML as opposed to de novo AML [8]; it has been proposed that ASXL1 mutations are implicated in dysplastic changes and ineffective hematopoiesis, without contributing directly to the acute leukemic transformation [8]. It is reported that ASXL1 mutations were detected more frequently in patients with secondary AML after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) as opposed to patients with primary AML or therapy-related AML [9]. A higher frequency of ASXL1 mutations has been observed in patients with essential thrombocytopenia (ET) who also had CALR mutations, compared with patients with JAK2 mutations (instead of CALR mutations); ASXL1 mutations correlated with lower median hemoglobin levels [10].

A study of 41 MDS patients who had progressed to either higher grade MDS or AML found a high frequency of concomitant ASXL1 and RUNX1 mutations [11]. In the pre-progression samples, all patients with RUNX1 mutations also had ASXL1 mutations; this was in contrast with patients without RUNX1 mutations where only approximately a third had ASXL1 mutations [11].

In patients with newly diagnosed AML, the presence of ASXL1 mutations have been found to be associated with older age and male gender [9,12]. In immunophenotypic analysis, ASXL1 mutated cases are found to have a stronger expression of CD13, CD34, CD133, and HLA-DR and a weaker expression of CD33, suggesting a more immature immunophenotype in ASXL1 mutated patients compared to ASXL1-wild type patients [9].

Compared to all other AML types, ASXL1 mutations are more frequently found in AML-MRC (myelodysplasia-related changes) [1]; the 2-year overall survival is worse in patients with AML-MRC with ASXL1 mutation, compared to those without the mutation [13].

Prognostic implications in myeloid neoplasms

Patients with ASXL1 mutations diagnosed with AML/MDS have a higher mortality rate compared with patients with AML/MDS without ASXL1 mutations [1]. The presence of ASXL1 mutations is associated with worse prognostic risk [14,15]. There is a higher leukemic transformation rate in ASXL1 mutated patients compared with ASXL1 wild type [16].

In patients with chronic myelomonocytic leukemia (CMML), ASXL1 frameshift and nonsense mutations are associated with a significantly lower overall survival [17]. In contrast, missense ASXL1 mutations do not appear to affect survival in CMML patients [1]. In patients with MDS, ASXL1 frameshift mutations are associated with worse overall survival whereas heterozygous point mutations are not [17].

In patients with primary myelofibrosis (PMF), there is significantly higher mortality in patients with ASXL1 mutations compared to ASXL1 wild type; ASXL1 mutations are associated with lower leukemia-free survival [18].

In de novo AML, patients with ASXL1 mutations had a significantly lower rate of complete remission after standard high-intensity chemotherapy; the median overall survival is significantly lower [12].

Therapeutic implications in myeloid neoplasms

In patients with CMML treated with hypomethylating agents, there is a shorter overall survival in subjects with ASXL1 mutations compared to ASXL1 wild type [19].

In cytogenetically normal AML patients receiving cytarabine-daunorubicin, there is a lower complete remission (CR) rate in patients with ASXL1 mutations compared to wild-type [20]. Among patients who achieve CR, those with ASXL1 mutations have shorter disease-free survival than ASXL1-wild type patients [20].

Stem cell transplantation is recommended in patients with PMF with presence of mutational status CALR-/ASXL+, as the mutational status is associated with a worse prognosis [21].

Colorectal cancer (CRC)

ASXL1 is frequently mutated in colorectal cancer cell lines with microsatellite instability (MSI) [22]. The G8 mononucleotide repeat at nucleotide position c.1927 to c.1934 of the ASXL1 gene is susceptible to the deletion or insertion of a G nucleotide as a result of MSI [22]. The deletion of c.1934G (c.1934delG) causes a frameshift and the insertion of G between c.1934 and c.1935 (c.1934_1935insG) causes a frameshift [22]. The c.1934_1935insG ASXL1 mutation is reported to be resistant to nonsense-mediated decay in CRC with MSI and consequently is predicted to be expressed as a C-terminally truncated protein [22].

Common Alteration Types

The majority of ASXL1 mutations are nonsense or frameshift variants causing truncation of downstream of the ASXH domain with consequent loss of the PHD domain [1]. Some of the common variants reported in the Catalogue of Somatic Mutations in Cancer database (COSMIC) (accessed 6th August 2018) are c.2444T>C (NM_015338.5) (p.L815P) (n=97) (all AML), c.2077C>T (NM_015338.5) (p.R693*) (majority hematological malignancies), c.1934_1935insG (NM_015338.5) (p.G646Wfs*12) (majority hematological malignancies).

Internal Pages

N/A

External Links

ASXL1 by Atlas of Genetics and Cytogenetics in Oncology – detailed gene information

ASXL1 by COSMIC – sequence information, expression, catalogue of mutations

ASXL1 by CIViC – general knowledge and evidence-based specific information

ASXL1 by Precision Medicine Knowledgebase (Weill Cornell) – manually vetted interpretations of variants and CNVs

ASXL1 by Cancer Genetics Web – gene, pathway, and publication information matched to cancer type

ASXL1 by OncoKB – mutational landscape, mutation effect, variant classification

ASXL1 by My Cancer Genome – brief gene overview

ASXL1 by UniProt – protein and molecular structure and function

ASXL1 by Pfam – gene and protein structure and function information

ASXL1 by GeneCards – general gene information and summaries

References

1. Alvarez Argote J, Dasanu CA, (2018). ASXL1 mutations in myeloid neoplasms: pathogenetic considerations, impact on clinical outcomes and survival. Curr Med Red Opin 34(5):757-763. PMID 28027687

2. Jacobs JJ, van Lohuizen M, (2002). Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim Biophys Acta 1602(2):151-61. PMID 12020801

3. Xiong B, et al., (2014). Characterization of side population cells isolated from the colon cancer cell line SW480. Int J Oncol 45(30:1175-1183. PMID 24926880

4. Fisher CL, et al., (2006). Characterization of Asxl1, a murine homolog of Additional sex combs, and analysis of the Asx-like gene family. Gene 369:109-118. PMID 16412590

5. Gelsi-Boyer V, et al., (2009). Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 145:788-800. PMID 19388938

6. Carbuccia N, et al., (2009). Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 23(11);2183-2186. PMID 19609284

7. Abdel-Wahab O, et al., (2012). ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 22(20):180-193. PMID 22897849

8. Lindsley RC, et al., (2015). Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 125(9):1367-1376. PMID 25550361

9. Schnittger S, et al., (2013). ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia 27(1):82-91. PMID 23018865

10. Shen H, et al., (2015). CALR and ASXL1 mutation analysis in 190 patients with essential thrombocythemia. Leuk Lymphoma 56(3):820-822. PMID 25005031

11. Pellagatti A, et al., (2016). Targeted resequencing analysis of 31 genes commonly mutated in myeloid disorders in serial samples from myelodysplastic syndrome patients showing disease progression. Leukemia 30(10:247-250. PMID 25991409

12. Chou WC, et al., (2010). Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like (ASXL1) mutations. Blood 116(20):4086-4094. PMID 20693432

13. Devillier R, et al., (2015). Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasic-related changes. Oncotarget 2015;6(10:8388-8396. PMID 25860933

14. Patnaik MM, et al., (2014). ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia 28(11):2206-2212. PMID 24695057

15. Patnaik MM, et al., (2013). Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia 27(7):1504-1510. PMID 23531518

16. Chen TC, et al., (2014). Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome. Blood Cancer J 4:e177. PMID 24442206

17. Thol F, et al., (2011). Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes. J Clin Oncol 29(18):2499-2506. PMID 21576631

18. Papaemmanuil E, et al., (2016). Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374(23):2209-2221. PMID 27276561

19. Itzykson R, et al., (2013). Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 31(19):2428-2436. PMID 23690417

20. Metzeler KH, et al., (2011). ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category. Blood 118(26):6920-6929. PMID 22031865

21. Tefferi A, et al., (2014). Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 89(9):915-925. PMID 25124313

22. Williams DS, et al., (2010). Nonsense mediated decay resistant mutations are a source of expressed mutant proteins in colon cancer cell lines with microsatellite instability. PLoS One 5(12):e16012. PMID 21209843

Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.