#### Atlas of Genetics and Cytogenetics in Oncology and Haematology

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## ABL

Identity

Other names | ABL1
Hugo | ABL1
Location | 9q34.1
| CAN is more telomeric, TAN1 even more in 9q34.3

DNA/RNA

| DNA diagram
Description | 12 exons; 230 kb
Transcription | alternate splicing: 1a and 1b are 5' alternative exons; mRNA of 6 and 7 kb (with 1a and 1b respectively), giving rise to 2 protein of 145 kDa

Protein

| Protein diagram

Description | 1130-1143 amino acids; 4 domains: of which are SH (SRC homology) domains; NH2-term -- domain 1: SH3 (where can bind the binding protein BP1, to inhibit SH1 activation) and SH2 (with high affinity towards BCR first exon) -- domain 2: SH1 (with a self-phosphorylable tyrosine) -- 'domain' 3: nuclear localization domain (DNA binding, but not during mitosis) -- domain 4: actin binding (cytoskeleton) --COOH-term; note: 1b (but not the 1a alternative) myristylable allowing anchorage to the membrane
Expression | ubiquitously expressed , c-ABL K/O phenotype is lethal
Localisation | nuclear and cytoplasmic
Function | c-ABL exhibit a permanent nuclear and cytoplasmic shuttling activity, driven by 3 nuclear localisation signals (NLS) and a single nuclear export signal (NES) close to the C-terminal region. Recent data suggest that nuclear and cytoplasmic ABL may have differnet functions. 1- Nuclear c-ABL plays a major role in the regulation of cell death after DNA damage. All DNA damage inducing agents activate nuclear c-ABL kinase in a ATM-dependent manner and in the presence of the p53-homolog p73 protein. The latter is physically associated with c-ABL after DNA damage through the SH3 domain of c-ABL. DNA damage also activates simultanously p53 pathway, leading to the activation of Rb which induces growth arrest and protects cells from apoptosis. The exacts mechanisms of apoptosis induced by c-ABL are unknown. The nuclear entrapment of BCR-ABL has also been shown to induce apoptosis in leukemic cells. 2- Cytoplasmic c-ABL : possible function in adhesion signalling as an efflux of c-ABL from nucleus to the cytoplasm is found in fibroblasts after adhesion.
Homology | SRC homology; like SRC, ABL is one of the tyrosine kinases which are not membrane receptors

Implicated in

Entity | t(9;12)(q34;p12)/ALL --> ETV6-ABL
Disease | common ALL; yet poorly known
Hybrid/Mutated Gene | 5' ETV6/TEL from 12p12 - 3' ABL from 9q34
Abnormal Protein | NH2-term Helix Loop Helix from ETV6(TEL) fused to Tyr Kinase from ABL COOH-term; localised in the cytoskeleton.
Oncogenesis | forms HLH-dependent oligomers, which may be critical for Tyr kinase activation; oncogenesis may be comparable to that induced by BCR/ABL
Entity | t(9;22)(q34;q11)/CML --> BCR/ABL
Disease | all CML have a t(9;22), at least at the molecular level (BCR/ABL); phenotype and stem cell origin: multipotent progenitor: t(9;22) is found in all myeloid and B- lineage progenitors
Prognosis | median survival => 4 yrs; alphaIFN therapy or BMT are indicated
Cytogenetics | anomalies additional to the t(9;22) may be found either at diagnosis or during course of the disease, or at the time of acute transformation; mainly: +der(22), +8, i(17q), +19; +21, -Y, -7, -17,+17; variant translocations: t(9;22;V) and apparent t(V;22) or t(9;V), where V is a variable chromosome, karyotypes with apparently normal chromosomes 9 and 22, may be found
| Probe 1132H12 on a case of CML with t(9/22). Note the splitting of the probe, evident also on interphase nuclei - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
Hybrid/Mutated Gene | see below
Abnormal Protein | see below
Oncogenesis | see below
Entity | t(9;22)(q34;q11)/ALL --> BCR/ABL
Disease | most often CD 10+ ALL; frequent CNS involvement
Prognosis | is very poor (BMT is indicated); the breakpiont in M-bcr or in m-bcr (see below) does not seem to have impact on prognosis
Cytogenetics | the chromosome anomaly t(9;22) disappear during remission, in contrast with BC-CML cases (CML in blast crisis); additional anomalies: +der(22), -7, del(7q) most often, +8, but not an i(17q), in contrast with CML and ANLL cases; complex karyotypes, often hyperploid; variants and complex translocations may be found as in CML
Hybrid/Mutated Gene | see below
Abnormal Protein | see below
Oncogenesis | see below
Entity | t(9;22)(q34;q11)/ANLL --> BCR/ABL
Disease | ANLL mostly M1 or M2 ANL
Prognosis | is very poor
Cytogenetics | the chromosome anomaly t(9;22) disappear during remission, in contrast with BC-CML cases (CML in blast crisis); additional anomalies: similar to what is found in CML
Hybrid/Mutated Gene | see below
Abnormal Protein | see below
Oncogenesis | see below
Hybrid/Mutated Gene | BCR/ABL the crucial event lies on der(22), id est 5' BCR - 3' ABL hybrid gene is the crucial one, while ABL/BCR may or may not be expressed; breakpoint in ABL is variable over a region of 200 kb, often between the two alternative exons 1b and 1a, sometimes 5' of 1b or 3' of 1a, but always 5' of exon 2; breakpoint in BCR is either: 1- in a region called M-bcr (for major breakpoint cluster region), a cluster of 5.8 kb, between exons 12 and 16, also called b1 to b5 of M- bcr; most breakpoints being either between b2 and b3, or between b3 and b4; transcript is 8.5 kb long; this results in a 210 KDa chimeric protein (P210); this is found in (most cases of) CML, and in half cases of ALL or ANLL HYBRID_GENE 2- in a 35 kb region between exons 1 and 2, called m-bcr (minor breakpoint cluster region), -> 7 kb mRNA, resulting in a 190 KDa protein (P190); this is found in half of the cases of ALL or ANLL 3- A breakpoint in the exon 19 of BCR (designed as micro-bcr) with fusion to abl sequences (a2) has been in neutrophilic CML, with presence of a larger protein (P230).
Abnormal Protein | BCR/ABL P210 comprises the first 902 or 927 amino acids from BCR, P190 only the 427 N-term from BCR; BCR/ABL has a cytoplasmic localization, in contrast with ABL, mostly nuclear
Oncogenesis | BCR/ABL has a cytoplasmic localization role and all three BCR-ABL fusion proteins have been shown to exhibit oncogenic potential. All three hybrid proteins have increased protein kinase activity compared to ABL: 3BP1 (binding protein) binds normal ABL on SH3 domain,which prevents SH1 activation; with BCR/ABL, the first (N-terminal) exon of BCR binds to SH2, hidding SH3 which, as a consequence, cannot be bound to 3BP1; thereof, SH1 is activated; oncogenesis 1- proliferation is induced through activation by BCR/ABL of RAS signal transduction pathway, PI3-K (phosphatidyl inositol 3' kinase) pathway, and MYC; 2- BCR/ABL inhibits apoptosis; 3- BCR/ABL provokes cell adhesive abnormalities

External links

| Nomenclature
Hugo | ABL1
GDB | ABL1
LocusLink | ABL1 25
| Cards
--- | ---
Atlas | ABL

GeneCards ABL1
Ensembl ABL1 - 9q34.1
CancerGene ABL1
Genatlas ABL1
GeneLynx ABL1
eGenome ABL1
euGene 25
Genomic and cartography
GoldenPath ABL1 - 9q34.1 chr9:128986497-129039105 + (hg16-July2003)
NCBI Genes Cyto Gene Seq [Map View - NCBI]
OMIM Disease map [OMIM]
HomoloGene ABL1
Gene and transcription
Genbank K00009 [ SRS ] K00009 [ ENTREZ ]
Genbank 13099 [ SRS ] 13099 [ ENTREZ ]
Genbank U07563 [ SRS ] U07563 [ ENTREZ ]
Genbank 14752 [ SRS ] 14752 [ ENTREZ ]
Genbank 14753 [ SRS ] 14753 [ ENTREZ ]
RefSeq NM_005157 [ SRS ] NM_005157 [ ENTREZ ]
RefSeq NM_007313 [ SRS ] NM_007313 [ ENTREZ ]
RefSeq NT_035014 [ SRS ] NT_035014 [ ENTREZ ]
AceView ABL1 AceView - NCBI
TRASER ABL1 Traser - Stanford
Unigene Hs.446504 [ SRS ] Hs.446504 [ NCBI ] HS446504 [ spliceNest ]
Protein : pattern, domain, 3D structure
SwissProt P00519 [ SRS] P00519 [ EXPASY ] P00519 [ INTERPRO ]
Prosite PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 PROTEIN_KINASE_ATP [ Expasy ]
Prosite PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 PROTEIN_KINASE_TYR [ Expasy ]
Prosite PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 PROTEIN_KINASE_DOM [ Expasy ]
Prosite PS50001 SH2 [ SRS ] PS50001 SH2 [ Expasy ]
Prosite PS50002 SH3 [ SRS ] PS50002 SH3 [ Expasy ]
Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ]
Interpro IPR000980 SH2 [ SRS ] IPR000980 SH2 [ EBI ]
Interpro IPR001452 SH3 [ SRS ] IPR001452 SH3 [ EBI ]
Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ]
Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ]
CluSTr P00519
Pfam PF00069 pkinase [ SRS ] PF00069 pkinase [ Sanger ] pfam00069 [ NCBI-CDD ]
Pfam PF00017 SH2 [ SRS ] PF00017 SH2 [ Sanger ] pfam00017 [ NCBI-CDD ]
Pfam PF00018 SH3 [ SRS ] PF00018 SH3 [ Sanger ] pfam00018 [ NCBI-CDD ]
Smart SM00252 SH2 [EMBL]
Smart SM00326 SH3 [EMBL]
Smart SM00219 TyrKc [EMBL]
Prodom PD000001 Prot_kinase[INRA-Toulouse]
Prodom P00519 ABL1_HUMAN [ Domain structure ] P00519 ABL1_HUMAN [ sequences sharing at least 1 domain ]
Prodom PD000001[INRA-Toulouse]
Prodom P00519 ABL1_HUMAN [ Domain structure ] P00519 ABL1_HUMAN [ sequences sharing at least 1 domain ]
Prodom PD000001[INRA-Toulouse]
Prodom P00519 ABL1_HUMAN [ Domain structure ] P00519 ABL1_HUMAN [ sequences sharing at least 1 domain ]
Blocks P00519
PDB 1AB2 [ SRS ] 1AB2 [ PdbSum ], 1AB2 [ IMB ]
PDB 2ABL [ SRS ] 2ABL [ PdbSum ], 2ABL [ IMB ]
PDB 1AWO [ SRS ] 1AWO [ PdbSum ], 1AWO [ IMB ]
PDB 1BBZ [ SRS ] 1BBZ [ PdbSum ], 1BBZ [ IMB ]
PDB 1ABL [ SRS ] 1ABL [ PdbSum ], 1ABL [ IMB ]
PDB 1JU5 [ SRS ] 1JU5 [ PdbSum ], 1JU5 [ IMB ]
Human PSD ABL1
PubGene ABL1
Polymorphism : SNP, mutations, diseases
OMIM 189980 [ map ]
SNP ABL1 [dbSNP-NCBI]
SNP NM_005157 [SNP-NCI]
SNP NM_007313 [SNP-NCI]
SNP ABL1 [GeneSNPs - Utah] ABL1 [SNP - CSHL] ABL1] [HGBASE - SRS]
General knowledge
Family Browser ABL1 [UCSC Family Browser]
SOURCE NM_005157
SOURCE NM_007313
SMD Hs.446504
SAGE Hs.446504
Enzyme 2.7.1.112 [ Enzyme-SRS ] 2.7.1.112 [ Brenda-SRS ] 2.7.1.112 [ KEGG ] 2.7.1.112 [ WIT ]
Amigo function|protein-tyrosine kinase activity
Amigo function|ATP binding
Amigo function|DNA binding
Amigo process|S-specific transcription in mitotic cell cycle
Amigo process|DNA damage response, signal transduction resulting in induction of apoptosis
Amigo process|mismatch repair
Amigo process|cell growth and/or maintenance
Amigo process|protein amino acid phosphorylation
Amigo process|regulation of transcription, DNA-dependent
Amigo process|intracellular signaling cascade
Amigo process|regulation of cell cycle
Amigo component|nucleus
Amigo function|transferase activity
Other databases
Probes
Probe ABL (9q34) in normal cells (Bari)
Probe ABL1 Related clones (RZPD - Berlin)
PubMed
PubMed 1 Pubmed reference(s) in LocusLink

Bibliography

The function of BCR/ABL and related proto-oncogenes
Gotoh A, Broxmeyer HE
Curr Opin Hematol 1997; 4: 3-11
Medline 97196352
Molecular insights into the Philadelphia translocation
Heisterkamp N, Groffen J
Hematol Pathol 1991; 5: 1-10
Medline 91267879
The molecular pathology of chronic myelogenous leukaemia
Kurzrock R, Talpaz M
Br J Haematol 1991; 79 Suppl 1: 34-37
Medline 92031068
Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase.
Taagepera S, McDonald D, Loeb JE, Whitaker LL, McElroy AK, Wang JYJ, Hope TJ.
Proc Natl Acad Sci USA 1998; 95 : 7457-7462.
Medline 9636171
The molecular biology of chronic myeloid leukemia.
Deininger MWN, Goldman JM, Melo JV
Blood 2000; 96: 3343-3356.
Medline 11071626
Regulation of cell death by the Abl tyrosine kinase.
Wang JYJ .
Oncogene 2000; 19 : 5643-5650.
Medline 11114745

REVIEW articles | automatic search in PubMed
Last year publications | automatic search in PubMed

CancerGene Bibliographic Citations

Contributor(s)

Written | 10-1997 | Jean-Loup Huret
Updated | 04-2001 | Ali G Turhan

Citation

This paper should be referenced as such :
Huret JL . ABL. Atlas Genet Cytogenet Oncol Haematol. October 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ABL.html
Turhan AG . ABL. Atlas Genet Cytogenet Oncol Haematol. April 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ABL.html

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