ASXL1 (additional sex combs like 1 (Drosophila))

2010-08-01   Marie-Joelle Mozziconacci  , Daniel Birnbaum  

Identity

HGNC
ASXL1
LOCATION
20q11.21
LOCUSID
171023
ALIAS
BOPS,MDS
FUSION GENES
Show Gene Fusions

DNA/RNA

Atlas Image
Representation of ASXL1 locus. A: Chromosome 20 with localisation of ASXL1; B: ASXL1 gene; C: Amino acid count; D: Protein with domains. ASXN, conserved domain at the N-terminus; ASXM, conserved domain in the middle part; NR, nuclear receptor; PHD, plant homeodomain; E: examples of mutations.

Description

The ASXL1 gene spans around 80 kb of genomic DNA and is composed of 12 exons.

Transcription

Alternative splicing results in multiple transcript variants.

Proteins

Description

The longer ASXL1 transcript encodes a 1541 amino acid (170 kDa) protein. Mammalian ASXL proteins are characterized by an amino-terminal ASX homology (ASXH) region containing 2 putative nuclear receptor coregulator binding motifs (NR box), 3 other NR box motifs and a C-terminal plant homeodomain protein-protein interaction domain. Contains one Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif, which may be required for an association with nuclear receptors.

Expression

ASXL1 is expressed all hematopoietic cell fractions in mice. Asxl1 knockout mice exhibit mild defects in differentiation of lymphoid and myeloid progenitors, but not in multipotent progenitors and do not develop MDS or other hematological malignancy.
ASXL1 is widely expressed at low level in heart, brain, skeletal muscle, placenta, pancreas, spleen, prostate, small intestine, colon, peripheral blood, leukocytes, bone marrow and fetal liver. Highly expressed in testes.

Localisation

Nucleus (probable).

Function

- ASXL1 acts as a co-regulator of retinoic acid (RA) receptor in RA sensitive cell lines, and as a co-repressor of RA receptor in RA resistant cell lines. Either a coactivator or corepressor for the retinoid receptors retinoic acid receptor and retinoid X receptor in a cell type-specific manner.
- ASXL1 cooperates with HP1 (heterochromatin protein 1) to modulate histone H3 demethylase LSD1 activity, leading to a change in histone H3 methylation and RAR repression.
- ASXL1 belongs to the Enhancer of Trithorax and Polycomb (ETP) group in drosophila.
- ASXL1 is required for maintenance of both activation and silencing of Hox genes in mice and drosophila in a context-dependent manner.
- ASXL1 is one of the fusion protein partners of PAX5 in B-cell precursor acute lymphoblastic leukemias.
- ASXL1 may function as a tumor suppressor in myeloid malignancies by affecting stem or progenitor cell self renewal or differentiation.

Homology

There are 3 mammalian homologs of the Additional sex combs (Asx) gene of Drosophila: ASXL1, 2 (chromosome 2p24 in humans) and 3 (chromosome 18q11 in humans).

Mutations

Note

Acquired ASXL1 mutations are frequently frameshift and nonsense. All mutations are in exon 12, mostly around the Gly-rich domain (amino acids 642-685). The most common somatic mutation is p.Gly646Trpfsx12.
These mutations cause truncation of the ASXL1 protein downstream of the ASXH domain leading to the loss of the C-terminal PHD domain.
Some possible single nucleotide polymorphisms have been described: p.Arg1224Thr, p.Thr769Ala, p.Gly1007Arg, p.Thr688Met, p.Gln1074Leu, p.Arg693Gly, p.T1139K, p.Gly652Ser, p.Val1072Asp...

All mutations have been found in myeloid diseases so far. A fusion has been found in B-cell leukemia.

Implicated in

Entity name
Myelodysplastic syndromes (11-21%)
Note
Mutations p.Arg596Profsx23, p.Gly646Trpfsx12 (the most common mutation), p.Gln1102Asp, p.Leu1395Val, p.Ser1457Profsx18...
Prognosis
More frequent in advanced and high-risk MDSs (>40% in RAEB2).
Cytogenetics
Normal or abnormal karyotype.
Entity name
Chronic myelomonocytic leukemia (33-43%)
Note
p.His630Profsx66, p.Lys618X, p.Gly646trpfsx12, p.Gln768X, p.Thr836Leufsx2, p.Ser846Glnfsx5, p.Lys888Glufsx6, p.Arg1068X, p.pro1263Glnfsx17, p.Leu1266Hisfsx9, p.Thr1271lysfsx10...
Prognosis
Associated with acute transformation.
Cytogenetics
Normal or abnormal karyotype. More common in patients with -7/7q-. Infrequent in the presence of -5/5q-.
Entity name
Juvenile myelomonocytic leukemia (JMML) (2/49 patients 4%)
Note
p.Arg693X, p.Ser846ValfsX21.
Cytogenetics
Normal karyotype or monosomy 7.
Entity name
Acute myeloid leukemia (20-30%)
Note
30% in primary AMLs, 47% in secondary AMLs and 23% in post-MDS AMLs.
Prognosis
Shorter overall survival.
Cytogenetics
Normal or abnormal karyotype, associated with trisomy 8, inversely correlated with NPM1 mutation.
Entity name
Myeloproliferative neoplasms (8%)
Note
Present in all forms, including chronic myeloid leukemia. More frequent in primary myelofibrosis.
Prognosis
Occur in both chronic and blast-phase MPNs.
Entity name
B-cell acute lymphoblastic leukemia
Cytogenetics
Dicentric chromosome dic(9;20)(p11-13;q11).
Hybrid gene
PAX5 on 9p and ASXL1 on 20q.

Article Bibliography

Pubmed IDLast YearTitleAuthors
200681842010Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.Abdel-Wahab O et al
200685722010Myelodysplastic syndromes: lost between two states?Acquaviva C et al
195869402009Heterogeneous breakpoints in patients with acute lymphoblastic leukemia and the dic(9;20)(p11-13;q11) show recurrent involvement of genes at 20q11.21.An Q et al
204109252010High-density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukemia during disease progression.Boultwood J et al
198651122010Mutual exclusion of ASXL1 and NPM1 mutations in a series of acute myeloid leukemias.Carbuccia N et al
166066172006Additional sex comb-like 1 (ASXL1), in cooperation with SRC-1, acts as a ligand-dependent coactivator for retinoic acid receptor.Cho YS et al
206934322010Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations.Chou WC et al
205924882010The molecular pathogenesis of myelodysplastic syndromes.Davids MS et al
201865052010Molecular aspects of myeloproliferative neoplasms.Delhommeau F et al
126574732003A human homolog of Additional sex combs, ADDITIONAL SEX COMBS-LIKE 1, maps to chromosome 20q11.Fisher CL et al
198331232010Additional sex combs-like 1 belongs to the enhancer of trithorax and polycomb group and genetically interacts with Cbx2 in mice.Fisher CL et al
198616792010Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia.Fisher CL et al
164125902006Characterization of Asxl1, a murine homolog of Additional sex combs, and analysis of the Asx-like gene family.Fisher CL et al
153755722004Identification and characterization of human CXXC10 gene in silico.Katoh M et al
198808792010ASXL1 represses retinoic acid receptor-mediated transcription through associating with HP1 and LSD1.Lee SW et al
205733982010The lower risk MDS patient at risk of rapid progression.Mittelman M et al
206782182010Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias.Rocquain J et al
185067482008Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: potential role in progression.Scotto L et al
204088412010Spectrum of molecular defects in juvenile myelomonocytic leukaemia includes ASXL1 mutations.Sugimoto Y et al
203349142010Spectrum of mutations in RARS-T patients includes TET2 and ASXL1 mutations.Szpurka H et al
204281942010Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Tefferi A et al

Other Information

Locus ID:

NCBI: 171023
MIM: 612990
HGNC: 18318
Ensembl: ENSG00000171456

Variants:

dbSNP: 171023
ClinVar: 171023
TCGA: ENSG00000171456
COSMIC: ASXL1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000171456ENST00000306058Q76L82
ENSG00000171456ENST00000375687Q8IXJ9
ENSG00000171456ENST00000375689Q5JWS8
ENSG00000171456ENST00000497249H0YJC9
ENSG00000171456ENST00000542461Q498B9
ENSG00000171456ENST00000555343A0A087WWN0
ENSG00000171456ENST00000613218Q8IXJ9
ENSG00000171456ENST00000620121Q8IXJ9
ENSG00000171456ENST00000642676A0A087WWN0
ENSG00000171456ENST00000643168A0A2R8Y627
ENSG00000171456ENST00000644587Q6P1M8
ENSG00000171456ENST00000645035A0A2R8Y6F0
ENSG00000171456ENST00000645337A0A2R8Y4U9
ENSG00000171456ENST00000645688A0A2R8Y6V0
ENSG00000171456ENST00000646367Q498B9
ENSG00000171456ENST00000646985A0A2R8Y5U1
ENSG00000171456ENST00000649901A0A087WWN0
ENSG00000171456ENST00000651418A0A494C1R1

Expression (GTEx)

0
10
20
30
40
50
60
70
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
DeubiquitinationREACTOMER-HSA-5688426
UCH proteinasesREACTOMER-HSA-5689603

References

Pubmed IDYearTitleCitations
379172392024Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models.1
379196072024ASXL1 mutation is a novel risk factor for bleeding in Philadelphia-negative myeloproliferative neoplasms.0
379210622024Comprehensive genomic profiling reveals molecular subsets of ASXL1-mutated myeloid neoplasms.1
382318812024Clonal haematopoiesis of indeterminate potential and atrial fibrillation: an east Asian cohort study.1
383409482024Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms.0
383590872024Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119.0
389269732024[Relationship between DTA Mutations and Thromboembolism in Patients with Myeloproliferative Neoplasms].0
379172392024Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models.1
379196072024ASXL1 mutation is a novel risk factor for bleeding in Philadelphia-negative myeloproliferative neoplasms.0
379210622024Comprehensive genomic profiling reveals molecular subsets of ASXL1-mutated myeloid neoplasms.1
382318812024Clonal haematopoiesis of indeterminate potential and atrial fibrillation: an east Asian cohort study.1
383409482024Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms.0
383590872024Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119.0
389269732024[Relationship between DTA Mutations and Thromboembolism in Patients with Myeloproliferative Neoplasms].0
364714772023Prognostic value of ASXL1 mutations in patients with myelodysplastic syndromes and acute myeloid leukemia: A meta-analysis.2

Citation

Marie-Joelle Mozziconacci ; Daniel Birnbaum

ASXL1 (additional sex combs like 1 (Drosophila))

Atlas Genet Cytogenet Oncol Haematol. 2010-08-01

Online version: http://atlasgeneticsoncology.org/gene/44553/gene-fusions/js/teaching-explorer/