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ASXL1 (additional sex combs like 1 (Drosophila))

Written2010-08Marie-Joelle Mozziconacci, Daniel Birnbaum
Institut Paoli-Calmettes, Centre de Recherche en Cancerologie de Marseille, Departement de Biopathologie, Laboratoire d'Oncologie Moleculaire, 232 Boulevard de Sainte-Marguerite, 13009 Marseille, France (MJM); Laboratoire d'Oncologie Moleculaire, Centre de Recherche en Cancerologie de Marseille, UMR891 Inserm, Institut Paoli-Calmettes 232 Boulevard de Sainte-Marguerite 13009 Marseille, France (BD)

(Note : for Links provided by Atlas : click)


Other aliasKIAA0978
LocusID (NCBI) 171023
Atlas_Id 44553
Location 20q11.21  [Link to chromosome band 20q11]
Location_base_pair Starts at and ends at bp from pter
Local_order centromere 5' - 3' telomere.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ASXL1 (20q11.21) / FTX (Xq13.2)ASXL1 (20q11.21) / PDRG1 (20q11.21)ASXL1 (20q11.21) / TM9SF4 (20q11.21)
ASXL1 (20q11.21) / XKR7 (20q11.21)ERBIN (5q12.3) / ASXL1 (20q11.21)HM13 (20q11.21) / ASXL1 (20q11.21)
NUDT16 (3q22.1) / ASXL1 (20q11.21)PAX5 (9p13.2) / ASXL1 (20q11.21)


  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.


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).


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 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 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 Juvenile myelomonocytic leukemia (JMML) (2/49 patients 4%)
Note p.Arg693X, p.Ser846ValfsX21.
Cytogenetics Normal karyotype or monosomy 7.
Entity 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 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 B-cell acute lymphoblastic leukemia
Cytogenetics Dicentric chromosome dic(9;20)(p11-13;q11).
Hybrid/Mutated Gene PAX5 on 9p and ASXL1 on 20q.

To be noted

ASXL1 can be altered by small local deletion detected only by array CGH or SNP arrays. However, ASXL1 seems to be centromeric to the main deleted region in classical 20q deletion.


Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.
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. 2010 Jan 15;70(2):447-52. Epub 2010 Jan 12.
PMID 20068184
Myelodysplastic syndromes: lost between two states?
Acquaviva C, Gelsi-Boyer V, Birnbaum D.
Leukemia. 2010 Jan;24(1):1-5.
PMID 20068572
Heterogeneous 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, Wright SL, Moorman AV, Parker H, Griffiths M, Ross FM, Davies T, Harrison CJ, Strefford JC.
Haematologica. 2009 Aug;94(8):1164-9. Epub 2009 Jul 7.
PMID 19586940
High-density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukemia during disease progression.
Boultwood J, Perry J, Zaman R, Fernandez-Santamaria C, Littlewood T, Kusec R, Pellagatti A, Wang L, Clark RE, Wainscoat JS.
Leukemia. 2010 Jun;24(6):1139-45. Epub 2010 Apr 22.
PMID 20410925
Mutual exclusion of ASXL1 and NPM1 mutations in a series of acute myeloid leukemias.
Carbuccia N, Trouplin V, Gelsi-Boyer V, Murati A, Rocquain J, Adelaide J, Olschwang S, Xerri L, Vey N, Chaffanet M, Birnbaum D, Mozziconacci MJ.
Leukemia. 2010 Feb;24(2):469-73. Epub 2009 Oct 29.
PMID 19865112
Additional sex comb-like 1 (ASXL1), in cooperation with SRC-1, acts as a ligand-dependent coactivator for retinoic acid receptor.
Cho YS, Kim EJ, Park UH, Sin HS, Um SJ.
J Biol Chem. 2006 Jun 30;281(26):17588-98. Epub 2006 Apr 10.
PMID 16606617
Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations.
Chou WC, Huang HH, Hou HA, Chen CY, Tang JL, Yao M, Tsay W, Ko BS, Wu SJ, Huang SY, Hsu SC, Chen YC, Huang YN, Chang YC, Lee FY, Liu MC, Liu CW, Tseng MH, Huang CF, Tien HF.
Blood. 2010 Aug 6. [Epub ahead of print]
PMID 20693432
The molecular pathogenesis of myelodysplastic syndromes.
Davids MS, Steensma DP.
Cancer Biol Ther. 2010 Aug 5;10(4). [Epub ahead of print]
PMID 20592488
Molecular aspects of myeloproliferative neoplasms.
Delhommeau F, Jeziorowska D, Marzac C, Casadevall N.
Int J Hematol. 2010 Mar;91(2):165-73. Epub 2010 Feb 27. (REVIEW)
PMID 20186505
A human homolog of Additional sex combs, ADDITIONAL SEX COMBS-LIKE 1, maps to chromosome 20q11.
Fisher CL, Berger J, Randazzo F, Brock HW.
Gene. 2003 Mar 13;306:115-26.
PMID 12657473
Additional sex combs-like 1 belongs to the enhancer of trithorax and polycomb group and genetically interacts with Cbx2 in mice.
Fisher CL, Lee I, Bloyer S, Bozza S, Chevalier J, Dahl A, Bodner C, Helgason CD, Hess JL, Humphries RK, Brock HW.
Dev Biol. 2010 Jan 1;337(1):9-15. Epub 2009 Oct 13.
PMID 19833123
Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia.
Fisher CL, Pineault N, Brookes C, Helgason CD, Ohta H, Bodner C, Hess JL, Humphries RK, Brock HW.
Blood. 2010 Jan 7;115(1):38-46. Epub 2009 Oct 27.
PMID 19861679
Characterization of Asxl1, a murine homolog of Additional sex combs, and analysis of the Asx-like gene family.
Fisher CL, Randazzo F, Humphries RK, Brock HW.
Gene. 2006 Mar 15;369:109-18. Epub 2006 Jan 18.
PMID 16412590
ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia.
Gelsi-Boyer V, Trouplin V, Rocquain J, Adelaide J, Carbuccia N, Esterni B, Finetti P, Murati M, Arnoulet C, Zerazhi H, Fezoui H, Tadrist Z, Nezri M, Chaffanet M, Mozziconacci MJ, Vey N, Birnbaum D.
British Journal of Haematology, 2010 Sept 29.
Identification and characterization of human CXXC10 gene in silico.
Katoh M, Katoh M.
Int J Oncol. 2004 Oct;25(4):1193-9.
PMID 15375572
ASXL1 represses retinoic acid receptor-mediated transcription through associating with HP1 and LSD1.
Lee SW, Cho YS, Na JM, Park UH, Kang M, Kim EJ, Um SJ.
J Biol Chem. 2010 Jan 1;285(1):18-29. Epub 2009 Oct 31.
PMID 19880879
The lower risk MDS patient at risk of rapid progression.
Mittelman M, Oster HS, Hoffman M, Neumann D.
Leuk Res. 2010 Jun 21. [Epub ahead of print]
PMID 20573398
Combined 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, Carbuccia N, Trouplin V, Raynaud S, Murati A, Nezri M, Tadrist Z, Olschwang S, Vey N, Birnbaum D, Gelsi-Boyer V, Mozziconacci MJ.
BMC Cancer. 2010 Aug 2;10:401.
PMID 20678218
Identification 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, Narayan G, Nandula SV, Arias-Pulido H, Subramaniyam S, Schneider A, Kaufmann AM, Wright JD, Pothuri B, Mansukhani M, Murty VV.
Genes Chromosomes Cancer. 2008 Sep;47(9):755-65.
PMID 18506748
Spectrum of molecular defects in juvenile myelomonocytic leukaemia includes ASXL1 mutations.
Sugimoto Y, Muramatsu H, Makishima H, Prince C, Jankowska AM, Yoshida N, Xu Y, Nishio N, Hama A, Yagasaki H, Takahashi Y, Kato K, Manabe A, Kojima S, Maciejewski JP.
Br J Haematol. 2010 Jul;150(1):83-7. Epub 2010 Apr 12.
PMID 20408841
Spectrum of mutations in RARS-T patients includes TET2 and ASXL1 mutations.
Szpurka H, Jankowska AM, Makishima H, Bodo J, Bejanyan N, Hsi ED, Sekeres MA, Maciejewski JP.
Leuk Res. 2010 Aug;34(8):969-73. Epub 2010 Mar 23.
PMID 20334914
Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.
Tefferi A.
Leukemia. 2010 Jun;24(6):1128-38. Epub 2010 Apr 29. (REVIEW)
PMID 20428194


This paper should be referenced as such :
Mozziconacci, MJ ; Birnbaum, D
ASXL1 (additional sex combs like 1 (Drosophila))
Atlas Genet Cytogenet Oncol Haematol. 2011;15(5):391-394.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 14 ]
  dic(9;20)(p13;q11) PAX5/ASXL1
dic(9;20)(p13;q11) PAX5/ASXL1
t(2;20)(p25;q11) TMEM18/ASXL1
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
Chronic Eosinophilic Leukemia-Not Otherwise Specified (CEL-NOS)::Idiopathic Hypereosinophilic Syndrome (IHES)
Classification of myelodysplastic syndromes 2015
Chronic Myelomonocytic Leukemia (CMML)
dic(9;20)(p11-13;q11) PAX5/Various
Mixed phenotype acute leukemia (MPAL)
Myelodysplastic/myeloproliferative neoplasms
Myelodysplastic syndrome with excess blasts
dic(9;20)(p13;q11) PAX5/ASXL1
dic(9;20)(p13;q11) PAX5/ASXL1
t(2;20)(p25;q11) TMEM18/ASXL1

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ]
  ASXL1/PDRG1 (20q11)
ASXL1/TM9SF4 (20q11)
ASXL1/XKR7 (20q11)

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)171023
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
Other database
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Oct 18 17:28:45 CEST 2018

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