Atlas of Genetics and Cytogenetics in Oncology and Haematology

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AML1 (acute myeloid leukemia 1)

RUNX1 (runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene))

CBFA2 (core binding factor A2)

Identity

Other namesPEBPaB (polyomavirus enhancer binding protein aB)
HGNC (Hugo) RUNX1
Location 21q22.3
Location_base_pair Starts at 35081968 and ends at 35182857 bp from pter ( according to hg18-Mar_2006)  [Mapping]
 
  AML1 (21q22.3) in normal cells: clone dJ1107L6 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are wellcome: contact M Rocchi

DNA/RNA

 
  DNA Diagram
Description the gene spans a region of more than 120 kb
Transcription transcription is from telomere to centromere --> the fusion gene is located on the 'other' chromosome (eg the der(8) of the t(8;21), the der(3) of the t(3;21)...); alternate splicing --> transcripts of 2, 3.3, ->7.5 and 8 kb

Protein

 
  Protein Diagram
Description 250, 453 amino acids and other forms; forms heterodimers with CBFB
Expression widely expressed, including hematopoietic cells at various stages of differenciation: role in haematopoiesis
Localisation nuclear
Function transcription factor (activator) for various hematopoietic-specific genes: binds to the core site 5' PyGPyGGTPy 3' of a number of promotors and enhancers, as in GM-CSF (granulocyte-macrophage colony stimulating factor, CSF1R (colony stimulating factor 1 receptor), TCRb sites (T cell antigen receptors), and myeloid myeloperoxidase
Homology 1- Runt (drosophila): nuclear DNA binding protein; role in segmentation (embryology); 2- AML2 (also called: CBFA3, CBFa3, PEBPaC), located in 1p35-36, expressed in B lineage (3 and 5 kb RNA); AML3: (also called: CBFA1, CBFa1, PEBPaA) in 6p21; 3- cbfa family (mouse)

Implicated in

Entity Familial platelet disorder with predisposition to acute non lymphocytic leukemia
  
Entity t(1;21)(p36;q22) treatment related acute non lymphocytic leukemia (ANLL) --> ?/ AML1
  
Entity t(2;21)(p11;q22) ANLL --> ?/ AML1
  
Entity t(3;21)(q26;q22)/ myelodysplastic syndrome (MDS) or ANLL --> -EVI1 or EAP/ MDS1 - AML1
Disease CML-BC of myeloid type; ANLL and MDS, often therapy related (secondary to antitopoisomerase II)
Hybrid/Mutated Gene 5' AML1 - 3' EAP or MDS1 or EVI1
  
Entity t(4;21)(q31;q22) T-cell acute lymphoblastic leukemia (T-ALL) --> ?/ AML1
  
Entity t(5;21)(q13;q22) myelodysplastic syndrome (MDS) and ANLL --> ?/ AML1
  
Entity t(8;21)(q22;q22)/ANLL. --> ETO - AML1
Disease ANLL, M2 mostly
Prognosis CR is obtained; median survival (1.5-2 yrs) is the range with other ANLL or relatively better
Cytogenetics additional anomalies are frequent: loss of Y or X chromosome, del(7q)/-7, +8, del (9q); complex t(8;21;Var) are known and have revealed that the crucial event lies on der(8); in agrement with the fact that both genes are transcribed from telomere to centromere
Hybrid/Mutated Gene 5' AML1 - 3' ETO
Abnormal Protein N-term AML1 with the Runt domain fused to the nearly entire ETO
Oncogenesis the fusion protein retain the ability to recognize the AML1 concensus binding site (--> negative dominant competitor with the normal AML1) and to dimerize with the cbtb/CBTB subunit --> probable altered transcriptional regulation of normal AML1 target genes
  
Entity t(8;21)(q23;q22) MDS --> FOG2 / AML1
  
Entity t(8;21)(q24;q22) ALL and ANLL --> TRPS1 / AML1
  
Entity t(12;21)(p13;q22)/ALL --> ETV6-AML1
Disease B cell ALL (CD10+)
Prognosis CR in all cases; prognosis seems good
Cytogenetics often undetectable without FISH; additional anomalies: frequent del(12)(p12) on the other allele
Hybrid/Mutated Gene 5' ETV6 - 3' AML1on the der(21)
Abnormal Protein Helix loop helix of TEL fused to the nearly entire AML1 protein; the other TEL allele is often deleted
  
Entity t(12;21)(q24;q22) ANLL --> ?/ AML1
  
Entity t(16;21)(q24;q22) ANLL --> MTG16-AML1
Disease ANLL and therapy related ANLL; mainly with preceeding MDS
Prognosis very poor
  
Entity t(17;21)(q11;q22) ANLL
  
Entity t(19;21)(q13;q22) treatment related ANLL --> AMP19 / AML1
  
Entity t(20;21)(q1;3q22) treatment related ANL --> ? / AML1
  
Entity t(21;21)(q11;q22) MDS --> UPS25 / AML1
  

Breakpoints

 

External links

Nomenclature
HGNC (Hugo)RUNX1   10471
Entrez_Gene (NCBI)RUNX1  861  runt-related transcription factor 1
Cards
AtlasAML1
GeneCards (Weizmann)RUNX1
Ensembl (Hinxton)ENSG00000159216 [Gene_View]  RUNX1 [Vega]
AceView (NCBI)RUNX1
Genatlas (Paris)RUNX1
euGene (Indiana)861
SOURCE (Stanford)NM_001001890 NM_001122607 NM_001754
Genomic and cartography
GoldenPath (UCSC)RUNX1  -  21q22.3   chr21:35081968-35182857 -  21q22.3   [Description]    (hg18-Mar_2006)
EnsemblRUNX1 - 21q22.3 [CytoView]
Mapping of homologs : NCBIRUNX1 [Mapview]
OMIM151385   180300   601399   601626   
Gene and transcription
Gene : Genbank (Entrez)AA878154 AK226159 AK310587 AL581043 AV761975
Reference sequence (RefSeq transcript) :SRSNM_001001890 NM_001122607 NM_001754
Reference transcript : EntrezNM_001001890 NM_001122607 NM_001754
RefSeq genomic : SRSAC_000064 AC_000153 NC_000021 NT_011512 NW_001838706 NW_927384
RefSeq genomic : EntrezAC_000064 AC_000153 NC_000021 NT_011512 NW_001838706 NW_927384
Consensus coding sequences : CCDS NCBIRUNX1
Cluster EST : UnigeneHs.612648 [ SRS ] Hs.612648 [ NCBI ]
Alternative Splicing : Fast-db (Paris)2368
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtQ01196 (SRS) Q01196 (Expasy) Q01196 (Uniprot)
With graphics : InterProQ01196
Splice isoforms : VarSplice FASTAQ01196(VarSplice FASTA)
Domaine pattern : Prosite (SRS)RUNT (PS51062)   
Domain pattern : Prosite (Expaxy)RUNT (PS51062)   
Domains : Interpro (SRS)AML1/Runt_N    AML1_Runt    p53_RUNT_DNA_bd    RunxI    TF_Runt-rel_RUNX   
Domains : Interpro (EBI)AML1/Runt_N    AML1_Runt    p53_RUNT_DNA_bd    RunxI    TF_Runt-rel_RUNX   
Related proteins : CluSTrQ01196
Domain families : Pfam SRSRunt (PF00853)    RunxI (PF08504)   
Domain families : Pfam SangerRunt (PF00853)    RunxI (PF08504)   
Domain families : Pfam NCBIpfam00853    pfam08504   
Blocks (Seattle)Q01196
Crystal structure of protein : PDB SRS1CMO    1CO1    1E50    1H9D    1LJM   
Crystal structure of protein : PDBSum1CMO    1CO1    1E50    1H9D    1LJM   
Crystal structure of protein : IMB1CMO    1CO1    1E50    1H9D    1LJM   
Crystal structure of protein : PDB RSDB1CMO    1CO1    1E50    1H9D    1LJM   
HPRD01043
Protein Interaction databases
DIP (DOE-UCLA)Q01196
IntAct (EBI)Q01196
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBIRUNX1
SNP : GeneSNP UtahRUNX1
SNP : HGBaseRUNX1
Genetic variants : HAPMAPRUNX1
Somatic Mutations in Cancer : COSMICRUNX1 
Translocation Breakpoints in Cancer : TICdbRUNX1 
Mutations and Diseases : HGMDRUNX1
Hereditary diseases : OMIM151385    180300    601399    601626   
Hereditary diseases : GENETests151385    180300    601399    601626   
Diseases : Genetic AssociationRUNX1
General knowledge
Homologs : HomoloGeneRUNX1
Homology/Alignments : Family Browser UCSCRUNX1
Phylogenetic Trees/Animal Genes : TreeFamRUNX1
Chemical/Protein Interactions : CTD861
Keywords Ontology : AmiGOtranscription factor activity  protein binding  ATP binding  nucleus  nucleus  regulation of transcription, DNA-dependent  multicellular organismal development  transcription activator activity  positive regulation of granulocyte differentiation  chloride ion binding  positive regulation of angiogenesis  positive regulation of transcription from RNA polymerase II promoter  
Keywords Ontology : EGO-EBItranscription factor activity  protein binding  ATP binding  nucleus  nucleus  regulation of transcription, DNA-dependent  multicellular organismal development  transcription activator activity  positive regulation of granulocyte differentiation  chloride ion binding  positive regulation of angiogenesis  positive regulation of transcription from RNA polymerase II promoter  
Pathways : BIOCARTA
Pathways : KEGG
Other databases
Probes
ProbeAML1 (21q22.3) in normal cells (Bari)
Probes : ImagenesRUNX1 Related clones (RZPD - Berlin)
Literature
PubMed242 Pubmed reference(s) in Entrez
PubGeneRUNX1

Bibliography

Molecular basis of the t(8;21) translocation in acute myeloid leukaemia.
Ohki M
Seminars in cancer biology. 1993 ; 4 (6) : 369-375.
PMID 8142622
 
AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia.
Nucifora G, Rowley JD
Blood. 1995 ; 86 (1) : 1-14.
PMID 7795214
 
High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia.
Romana SP, Poirel H, Leconiat M, Flexor MA, Mauchauffˆ© M, Jonveaux P, Macintyre EA, Berger R, Bernard OA
Blood. 1995 ; 86 (11) : 4263-4269.
PMID 7492786
 
CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy.
Roulston D, Espinosa R 3rd, Nucifora G, Larson RA, Le Beau MM, Rowley JD
Blood. 1998 ; 92 (8) : 2879-2885.
PMID 9763573
 
Combined spectral karyotyping and DAPI banding analysis of chromosome abnormalities in myelodysplastic syndrome.
Kakazu N, Taniwaki M, Horiike S, Nishida K, Tatekawa T, Nagai M, Takahashi T, Akaogi T, Inazawa J, Ohki M, Abe T
Genes, chromosomes & cancer. 1999 ; 26 (4) : 336-345.
PMID 10534769
 
A new angle on a pervasive oncogene.
Cleary ML
Nature genetics. 1999 ; 23 (2) : 134-135.
PMID 10508502
 
Concurrent translocations of MLL and CBFA2 (AML1) genes with new partner breakpoints in a child with secondary myelodysplastic syndrome after treatment of acute lymphoblastic leukemia.
Mathew S, Head D, Rubnitz JE, Raimondi SC
Genes, chromosomes & cancer. 2000 ; 28 (2) : 227-232.
PMID 10825008
 
Identification of two new translocations that disrupt the AML1 gene.
Richkind K, Hromas R, Lytle C, Crenshaw D, Velasco J, Roherty S, Srinivasiah J, Varella-Garcia M
Cancer genetics and cytogenetics. 2000 ; 122 (2) : 141-143.
PMID 11106827
 
A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations.
Hromas R, Shopnick R, Jumean HG, Bowers C, Varella-Garcia M, Richkind K
Blood. 2000 ; 95 (12) : 4011-4013.
PMID 10845943
 
A novel CBFA2 single-nucleotide mutation in familial platelet disorder with propensity to develop myeloid malignancies.
Buijs A, Poddighe P, van Wijk R, van Solinge W, Borst E, Verdonck L, Hagenbeek A, Pearson P, Lokhorst H
Blood. 2001 ; 98 (9) : 2856-2858.
PMID 11675361
 
Novel cryptic, complex rearrangements involving ETV6-CBFA2 (TEL-AML1) genes identified by fluorescence in situ hybridization in pediatric patients with acute lymphoblastic leukemia.
Mathew S, Shurtleff SA, Raimondi SC
Genes, chromosomes & cancer. 2001 ; 32 (2) : 188-193.
PMID 11550288
 
AML1-TRPS1 chimeric protein is generated by t(8;21)(q24;q22) in relapsing acute myeloblastic leukemia.
Asou N, Matsuno N, Mitsuya H
Am Soc Hematol,. 1943.
 
In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis.
Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N, Shigesada K, Ito Y, Benson KF, Raskind WH, Rossier C, Antonarakis SE, Israels S, McNicol A, Weiss H, Horwitz M, Scott HS
Blood. 2002 ; 99 (4) : 1364-1372.
PMID 11830488
 
A new translocation that rearranges the AML1 gene in a patient with T-cell acute lymphoblastic leukemia.
Mikhail FM, Serry KA, Hatem N, Mourad ZI, Farawela HM, El Kaffash DM, Coignet L, Nucifora G
Cancer genetics and cytogenetics. 2002 ; 135 (1) : 96-100.
PMID 12072207
 
High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia.
Romana SP, et al.
Blood. 1995 Dec 1;86(11):4263-9.
PMID 7492786
 
CBFA2(AML1) Translocations With Novel Partner Chromosomes in Myeloid Leukemias: Association With Prior Therapy.
Roulston D, Espinosa IIIR, Nucifora G, Larson RA, Le Beau MM, Rowley JD.
Blood 1998; 92: 2879-2885.
 
Combined spectral karyotyping and DAPI banding analysis of chromosome abnormalities in myelodysplastic syndrome.
Kakazu N, Taniwaki M, Horiike S, Nishida K, Tatekawa T, Nagai M, Takahashi T, Akaogi T, Inazawa J, Ohki M, Abe T.
Genes Chromosomes Cancer 1999; 26: 336-345.
 
Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.
Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, Ratajczak J, Resende IC, Haworth C, Hock R, Loh M, Felix C, Roy DC, Busque L, Kurnit D, Willman C, Gewirtz AM, Speck NA, Bushweller JH, Li FP, Gardiner K, Poncz M, Maris JM, Gilliland DG.
Nat Genet. 1999;23:134-135.
 
Concurrent translocations of MLL and CBFA2 (AML1) genes with new partner breakpoints in a child with secondary myelodysplastic syndrome after treatment of acute lymphoblastic leukemia.
Mathew S, Head D, Rubnitz JE, Raimondi SC.
Genes Chromosomes Cancer 2000; 28: 227-232.
PMID 10825008
 
Identification of two new translocations that disrupt the AML1 gene.
Richkind K, Hromas R, Lytle C, Crenshaw D, Velasco J, Roherty S, Srinivasiah J, Varella-Garcia M.
Cancer Genet Cytogenet 2000; 122: 141-143.
 
A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations
Hromas R, Shopnick R, Jumean HG, Bowers C, Varella-Garcia M, Richkind K.
Blood 2000; 95:4011-4013
 
A novel CBFA2 single-nucleotide mutation in familial platelet disorder with propensity to develop myeloid malignancies.
Buijs A, Poddighe P, van Wijk R, van Solinge W, Borst E, Verdonck L, Hagenbeek A, Pearson P, Lokhorst H.
Blood 2001; 98:2856-2858.
 
Novel cryptic, complex rearrangements involving ETV6-CBFA2 (TEL-AML1) genes identified by fluorescence in situ hybridization in pediatric patients with acute lymphoblastic leukemia.
Mathew S, Shurtleff SA, Raimondi SC.
Genes Chromosomes Cancer. 2001; 32: 188-193.
PMID 11550288
 
AML1-TRPS1 chimeric protein is generated by t(8;21)(q24;q22) in relapsing acute myeloblastic leukemia.
Asou N, Matsuno N, Mitsuya H.
Am Soc Hematol, 43 Annual meeting, Blood 2001; 98 11: 564a.
 
In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis.
Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N, Shigesada K, Ito Y, Benson KF, Raskind WH, Rossier C, Antonarakis SE, Israels S, McNicol A, Weiss H, Horwitz M, Scott HS.
Blood 2002;99:1364-1372.
 
A new translocation that rearranges the AML1 gene in a patient with T-cell acute lymphoblastic leukemia.
Mikhail FM, Serry KA, Hatem N, Mourad ZI, Farawela HM, El Kaffash DM, Coignet L, Nucifora G.
Cancer Genet Cytogenet 2002; 135: 96-100.
 
Molecular basis of the t(8;21) translocation in acute myeloid leukaemia.
Ohki M
Seminars in cancer biology. 1993 ; 4 (6) : 369-375.
PMID 8142622
 
AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia.
Nucifora G, Rowley JD
Blood. 1995 ; 86 (1) : 1-14.
PMID 7795214
 
High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia.
Romana SP, Poirel H, Leconiat M, Flexor MA, Mauchauffˆ© M, Jonveaux P, Macintyre EA, Berger R, Bernard OA
Blood. 1995 ; 86 (11) : 4263-4269.
PMID 7492786
 
CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy.
Roulston D, Espinosa R 3rd, Nucifora G, Larson RA, Le Beau MM, Rowley JD
Blood. 1998 ; 92 (8) : 2879-2885.
PMID 9763573
 
Combined spectral karyotyping and DAPI banding analysis of chromosome abnormalities in myelodysplastic syndrome.
Kakazu N, Taniwaki M, Horiike S, Nishida K, Tatekawa T, Nagai M, Takahashi T, Akaogi T, Inazawa J, Ohki M, Abe T
Genes, chromosomes & cancer. 1999 ; 26 (4) : 336-345.
PMID 10534769
 
A new angle on a pervasive oncogene.
Cleary ML
Nature genetics. 1999 ; 23 (2) : 134-135.
PMID 10508502
 
Concurrent translocations of MLL and CBFA2 (AML1) genes with new partner breakpoints in a child with secondary myelodysplastic syndrome after treatment of acute lymphoblastic leukemia.
Mathew S, Head D, Rubnitz JE, Raimondi SC
Genes, chromosomes & cancer. 2000 ; 28 (2) : 227-232.
PMID 10825008
 
Identification of two new translocations that disrupt the AML1 gene.
Richkind K, Hromas R, Lytle C, Crenshaw D, Velasco J, Roherty S, Srinivasiah J, Varella-Garcia M
Cancer genetics and cytogenetics. 2000 ; 122 (2) : 141-143.
PMID 11106827
 
A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations.
Hromas R, Shopnick R, Jumean HG, Bowers C, Varella-Garcia M, Richkind K
Blood. 2000 ; 95 (12) : 4011-4013.
PMID 10845943
 
A novel CBFA2 single-nucleotide mutation in familial platelet disorder with propensity to develop myeloid malignancies.
Buijs A, Poddighe P, van Wijk R, van Solinge W, Borst E, Verdonck L, Hagenbeek A, Pearson P, Lokhorst H
Blood. 2001 ; 98 (9) : 2856-2858.
PMID 11675361
 
Novel cryptic, complex rearrangements involving ETV6-CBFA2 (TEL-AML1) genes identified by fluorescence in situ hybridization in pediatric patients with acute lymphoblastic leukemia.
Mathew S, Shurtleff SA, Raimondi SC
Genes, chromosomes & cancer. 2001 ; 32 (2) : 188-193.
PMID 11550288
 
AML1-TRPS1 chimeric protein is generated by t(8;21)(q24;q22) in relapsing acute myeloblastic leukemia.
Asou N, Matsuno N, Mitsuya H
Am Soc Hematol,. 1943.
 
In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis.
Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N, Shigesada K, Ito Y, Benson KF, Raskind WH, Rossier C, Antonarakis SE, Israels S, McNicol A, Weiss H, Horwitz M, Scott HS
Blood. 2002 ; 99 (4) : 1364-1372.
PMID 11830488
 
A new translocation that rearranges the AML1 gene in a patient with T-cell acute lymphoblastic leukemia.
Mikhail FM, Serry KA, Hatem N, Mourad ZI, Farawela HM, El Kaffash DM, Coignet L, Nucifora G
Cancer genetics and cytogenetics. 2002 ; 135 (1) : 96-100.
PMID 12072207
 
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Contributor(s)

Written11-1997Jean-Loup Huret
Updated12-1997Jean-Loup Huret
Updated01-2003Jean-Loup Huret and Sylvie Senon

Citation

This paper should be referenced as such :
Huret JL . AML1 (acute myeloid leukemia 1); RUNX1 (runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)); CBFA2 (core binding factor A2). Atlas Genet Cytogenet Oncol Haematol. November 1997 .
URL : http://AtlasGeneticsOncology.org/Genes/AML1.html
Huret JL . AML1 (acute myeloid leukemia 1); RUNX1 (runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)); CBFA2 (core binding factor A2). Atlas Genet Cytogenet Oncol Haematol. December 1997 .
URL : http://AtlasGeneticsOncology.org/Genes/AML1.html
Huret JL, Senon S . AML1 (acute myeloid leukemia 1); RUNX1 (runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)); CBFA2 (core binding factor A2). Atlas Genet Cytogenet Oncol Haematol. January 2003 .
URL : http://AtlasGeneticsOncology.org/Genes/AML1.html

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indexed on : Sat Jun 27 16:39:26 CEST 2009
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