ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)

2008-08-01 Ali G Turhan Affiliation

Pole de Biologie-Sante - 40 avenue du Recteur Pineau - 86022 Poitiers Cedex, France

Identity

HGNC

ABL1

LOCATION

9q34.12

LOCUSID

FUSION GENES

Show Gene Fusions

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.

Proteins

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.
Normal ABL has a tri-dimensional structure which is tightly preserved in a closed, inactive conformation order to prevent oncogenic activation. The maintenance of this inactive conformation is possible by:

1- the "latching" of the myristilated NH2-terminal sequence which is directly linked to a myristilation recognition sequence on the c-lobe of the SH1 kinase domain;

2-The close contact between SH3 and SH2 domain

3- The interactions between SH3 domain and the C-lobe of the kinase domain. These interactions clamp the structure and prevent the kinase to switch to an active conformation, a process which requires the phosphorylation of Tyr 412 residue and the "unlatching" of the myristoyl group from the C-Lobe of the kinase domain. The attachment of proline-rich SH2 and SH3 ligands leads to the complete switch of the protein to an open, active conformation of the kinase. The NH2-terminal myristilation (autoregulatory role) is deleted during the t(9;22) translocation.

Expression

Ubiquitously expressed, c-ABL K/O phenotype is lethal.

Localisation

c-abl is localized to the nucleus, plasma membrane and actin cytoskeleton.

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 different 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 translocation of cytoplasmic c-ABL to the nucleus has been shown to be due to its release from 14-3-3 proteins to which c-ABL is associated in the cytoplasm. JNK-dependent phosphorylation of 14-3-3 upon an oxidative stress, allows this release process and translocation of c-ABL to the nucleus. The oncoprotein MUC has also been shown to block nuclear translocation of c-ABL after apoptotic stimuli.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. Regulation: Experiments using purified c-abl in vitro allowed to elucidate the mechanism of c-abl regulation which is mediated by an intrinsic property of the molecule. This is the 80 amino-acid N terminal "cap" of the protein is able and sufficient its tyrosine kinase activity and the loss of this cap portion activates the oncogenic potential of c-abl. From the structural point of view, this inhibition is generated by the docking of the myristilated N-terminal of c-abl into the kinase domain. The current view is the fact that c-abl localized in the nucleus, plasma membrane and the actin cytoskeleton undergo different types of regulation. In the membrane-associated c-abl, the myristilated N-terminal end of membrane form can not interact with the kinase c-lobe and it has been suggested that phosphadytilinositol 4-5 bi-phosphate could play an inhibitory role. The autoregulatory mechanism remains functional in the cytoplasmic and nuclear form of c-abl. The latter is also negatively regulated by Rb in the G-phase of the cell cycle. Beside the structural auto-inhibition, several cellular proteins have been shown to inhibit c-ABL: Pag (or Peroxiredoxin-I), Rb and F(actin). Regulation of ABL could therefore be due to a dual mechanism, involving an autoinhibition in the presence of co-inhibitors, which can be active on normal ABL-kinase activity but inactive against increased TK activity of BCR-ABL proteins.
Recent data suggest that pharmacological inhibition of endogenous ABL could lead to a genetic instability, potentially by inhibition of mismatch repair mechanisms. Long-term inhibition of c-ABL by TKI therapies could therefore be responsible of the occurrence of a mutator phenotypes.
Activation of ABL can also be detected in solid malignant tumors (lung and breast). Similarly , it has been shown that tumor suppression induced by Ephrin receptor EphB4 requires the presence of an active ABL and phosphorylation of the downstream target CRK by ABL.

Homology

SRC homology; like SRC, ABL is one of the tyrosine kinases which are not membrane receptors.

Implicated in

Entity name

t(9;12)(q34;p12)/acute lymphoblastic leukemia (ALL) --> ETV6-ABL1

Disease

Common ALL; yet poorly known.

Hybrid gene

5 ETV6/TEL from 12p12 - 3 ABL from 9q34.

Fusion 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 name

t(9;22)(q34;q11)/chronic myelogenous leukemia (CML) --> BCR/ABL1

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

The prognosis of CML has changed radically over the last 10 years, due to the development of novel drugs able to target the enhanced tyrosine kinase activity of BCR-ABL. The first of these therapies is Imatinib Mesylate (Gleevec) which has become the first line therapy for all patients with CML (See CML). In the first cohort trial of patients treated with Imatinib mesylate, the rates of complete cytogenetics responses (CCR) were exceptionally high (82 %) as compared to standard IFN-alpha - ARA-C therapy. At the most recent 6-year update, the overall survival is 90 % and most interestingly, the rates of progression towards more aggressive phases have been found to be progressively decreasing in all patients with major molecular responses (MMR). (For definition of MMR see CML). In IM-resistant or relapsing Ph1+ CML patients, second generation tyrosine kinase inhibitor (TKI) therapies such as Dasatinib (a dual SRC and ABL inhibitor) and Nilotinib have also recently become available.

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.

Hybrid gene

see below

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

Fusion protein

see below

Oncogenesis

see below

Entity name

t(9;22)(q34;q11)/ALL --> BCR/ABL1

Disease

Most often CD 10+ B-ALL; frequent CNS involvement.

Prognosis

The prognosis of Ph1+ ALL has changed since the introduction of tyrosine-kinase inhibitor therapies, especially imatinib mesylate which is currently used as a first line therapy associated with either high dose chemotherapy or classical ALL-type induction (steroids+ vincristine) and maintenance. Allogeneic stem cell transplantation is indicated in Ph1+ ALL patients relapsing after Imatinib-based regimens. In IM-resistant or relapsing Ph1+ ALL patients, second generation tyrosine kinase inhibitor (TKI) therapies such as Dasatinib (a dual SRC and ABL inhibitor) and Nilotinib have also recently become available.

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 AML cases; complex karyotypes, often hyperploid; variants and complex translocations may be found as in CML.

Hybrid gene

see below. In Both CML and Ph1+ ALL, detection and quantification of p210 BCR-ABL and p190 BCR-ABL have become the cornerstones of monitoring targeted therapies.

Fusion protein

see below

Oncogenesis

see below

Entity name

t(9;22)(q34;q11)/acute myeloid leukemia (AML) --> BCR/ABL1

Disease

AML mostly M1 or M2 AML.

Prognosis

High rates of hematologic , cytogenetic and molecular responses have been reported in de novo PH1+ AML, which is a rare entity.

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 gene

see below

Fusion protein

see below

Oncogenesis

see below

Hybrid 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 AML.

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 AML.

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).

Fusion 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 (via activation of STAT5 and BclXL)
3- BCR/ABL provokes cell adhesive abnormalities (via CRK-L, FAK) as well as abnormalities of cell migration (via CXCR-4 whose expression is downregulated in CML cells expressing high levels of BCR-ABL).
In experimental settings CD44 has been shown to play a major role in homing of BCR-ABL expressing cells.
4- BCR-ABL induces a major genetic instability: Molecular pathways involved in this phenomenon have recently been elucidated (See BCR-ABL).
5-BCR-ABL and endogenous ABL have been shown to be the target of miR 203 which is heavily methylated in CML cell lines expressing BCR-ABL. Restoration of miR 203 expression leads to reduction of BCR-ABL levels, suggesting a potential use of this strategy for therapeutic purposes.

Breakpoints

Article Bibliography

Pubmed ID	Last Year	Title	Authors
18538733	2008	Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression.	Bueno MJ et al
14982876	2004	The biology of CML blast crisis.	Calabretta B et al
11071626	2000	The molecular biology of chronic myeloid leukemia.	Deininger MW et al
15805265	2005	p210BCR-ABL inhibits SDF-1 chemotactic response via alteration of CXCR4 signaling and down-regulation of CXCR4 expression.	Geay JF et al
16998483	2006	Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells.	Krause DS et al
18391983	2008	Activated c-Abl tyrosine kinase in malignant solid tumors.	Lin J et al
12654251	2003	Structural basis for the autoinhibition of c-Abl tyrosine kinase.	Nagar B et al
16862147	2006	The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway.	Noren NK et al
11753385	2002	BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2.	Perrotti D et al
11832214	2002	Autoinhibition of c-Abl.	Pluk H et al
16888623	2006	MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage.	Raina D et al
15039778	2004	Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced Rac activation.	Sini P et al
12906815	2003	c-Abl regulation: a tail of two lipids.	Van Etten RA et al
18480061	2008	Role of c-Abl kinase in DNA mismatch repair-dependent G2 cell cycle checkpoint arrest responses.	Wagner MW et al
14704671	2004	Controlling Abl: auto-inhibition and co-inhibition?	Wang JY et al
15032571	2004	The BCR-ABL story: bench to bedside and back.	Wong S et al
15696159	2005	JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage.	Yoshida K et al

Other Information

Locus ID:

NCBI: 25
MIM: 189980
HGNC: 76
Ensembl: ENSG00000097007

Variants:

dbSNP: 25
ClinVar: 25
TCGA: ENSG00000097007
COSMIC: ABL1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000097007	ENST00000318560	P00519
ENSG00000097007	ENST00000318560	A0A024R8E2
ENSG00000097007	ENST00000372348	P00519
ENSG00000097007	ENST00000393293	R4GRW0

Expression (GTEx)

100

150

200

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

Pathway	Source	External ID
ErbB signaling pathway	KEGG	ko04012
Cell cycle	KEGG	ko04110
Axon guidance	KEGG	ko04360
Pathogenic Escherichia coli infection	KEGG	ko05130
Chronic myeloid leukemia	KEGG	ko05220
ErbB signaling pathway	KEGG	hsa04012
Cell cycle	KEGG	hsa04110
Axon guidance	KEGG	hsa04360
Pathogenic Escherichia coli infection	KEGG	hsa05130
Shigellosis	KEGG	hsa05131
Pathways in cancer	KEGG	hsa05200
Chronic myeloid leukemia	KEGG	hsa05220
Neurotrophin signaling pathway	KEGG	ko04722
Neurotrophin signaling pathway	KEGG	hsa04722
Viral myocarditis	KEGG	hsa05416
MicroRNAs in cancer	KEGG	hsa05206
MicroRNAs in cancer	KEGG	ko05206
Ras signaling pathway	KEGG	hsa04014
Immune System	REACTOME	R-HSA-168256
Innate Immune System	REACTOME	R-HSA-168249
Fcgamma receptor (FCGR) dependent phagocytosis	REACTOME	R-HSA-2029480
Regulation of actin dynamics for phagocytic cup formation	REACTOME	R-HSA-2029482
Hemostasis	REACTOME	R-HSA-109582
Factors involved in megakaryocyte development and platelet production	REACTOME	R-HSA-983231
Signal Transduction	REACTOME	R-HSA-162582
Signaling by Rho GTPases	REACTOME	R-HSA-194315
RHO GTPase Effectors	REACTOME	R-HSA-195258
RHO GTPases Activate WASPs and WAVEs	REACTOME	R-HSA-5663213
Developmental Biology	REACTOME	R-HSA-1266738
Axon guidance	REACTOME	R-HSA-422475
Signaling by Robo receptor	REACTOME	R-HSA-376176
Role of Abl in Robo-Slit signaling	REACTOME	R-HSA-428890
Myogenesis	REACTOME	R-HSA-525793
CDO in myogenesis	REACTOME	R-HSA-375170
DNA Repair	REACTOME	R-HSA-73894
DNA Double-Strand Break Repair	REACTOME	R-HSA-5693532
DNA Double Strand Break Response	REACTOME	R-HSA-5693606
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	REACTOME	R-HSA-5693565
Homology Directed Repair	REACTOME	R-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)	REACTOME	R-HSA-5693567
HDR through Single Strand Annealing (SSA)	REACTOME	R-HSA-5685938

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PMIDs
PA10804	imatinib	Chemical	LabelAnnotation, VipGene	associated
PA162372878	dasatinib	Chemical	LabelAnnotation, VipGene	associated
PA164924493	axitinib	Chemical	VipGene	associated	25686603
PA165958345	nilotinib	Chemical	LabelAnnotation, VipGene	associated
PA165980594	ponatinib	Chemical	LabelAnnotation, VipGene	associated
PA166114906	bosutinib	Chemical	LabelAnnotation, VipGene	associated
PA166114929	homoharringtonine	Chemical	LabelAnnotation	associated
PA166129524	blinatumomab	Chemical	LabelAnnotation	associated
PA166157848	rs121913459	Variant	LabelAnnotation, VipGene	associated	25686603, 15256671
PA166177510	inotuzumab ozogamicin	Chemical	LabelAnnotation	associated
PA445062	Neoplasms	Disease	MultilinkAnnotation	associated	2676087
PA445316	Philadelphia Chromosome	Disease	MultilinkAnnotation, VipGene	associated	6960256, 2676087, 6960256
PA446171	Leukemia, Myelogenous, Chronic, BCR-ABL Positive	Disease	MultilinkAnnotation, VipGene	associated	6960256, 2676087, 6960256
PA446175	Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative	Disease	MultilinkAnnotation	associated	2676087
PA448691	busulfan	Chemical	LabelAnnotation	associated
PA451879	vincristine	Chemical	LabelAnnotation	associated

References

Pubmed ID	Year	Title	Citations
38153913	2024	Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL.	3
38236369	2024	A case report of a truncated ABL1 mutation in 2 cases with Philadelphia chromosome-positive B cell precursor acute lymphoblastic leukemia.	0
38325182	2024	Zinc as a potential regulator of the BCR-ABL oncogene in chronic myelocytic leukemia cells.	0
38441775	2024	Characteristics and literature review of ETV6::ABL1 fusion gene-positive acute myeloid leukemia.	0
38743093	2024	Human ABL1 deficiency syndrome (HADS) is a recognizable syndrome distinct from ABL1-related congenital heart defects and skeletal malformations syndrome.	0
38153913	2024	Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL.	3
38236369	2024	A case report of a truncated ABL1 mutation in 2 cases with Philadelphia chromosome-positive B cell precursor acute lymphoblastic leukemia.	0
38325182	2024	Zinc as a potential regulator of the BCR-ABL oncogene in chronic myelocytic leukemia cells.	0
38441775	2024	Characteristics and literature review of ETV6::ABL1 fusion gene-positive acute myeloid leukemia.	0
38743093	2024	Human ABL1 deficiency syndrome (HADS) is a recognizable syndrome distinct from ABL1-related congenital heart defects and skeletal malformations syndrome.	0
36180046	2023	Emergence of a BCR::ABL1 rearrangement following a uniquely complex clonal evolution pattern in a patient undergoing Fms-like tyrosine kinase 3 inhibitor therapy for acute myeloid leukemia.	0
36324283	2023	Extramedullary T-lymphoblastic blast crisis in chronic myeloid leukemia: A very rare case associated with comutation of ABL1 T315I and H396R.	0
36719792	2023	BH3 mimetics and TKI combined therapy for Chronic Myeloid Leukemia.	0
36871092	2023	The interplay between telomeric complex members and BCR::ABL1 oncogenic tyrosine kinase in the maintenance of telomere length in chronic myeloid leukemia.	0
37071594	2023	Abl kinase-mediated FUS Tyr526 phosphorylation alters nucleocytoplasmic FUS localization in FTLD-FUS.	2

Citation

Ali G Turhan

ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)

Atlas Genet Cytogenet Oncol Haematol. 2008-08-01

Online version: http://atlasgeneticsoncology.org/gene/1/abl1

Historical Card

2001-04-01 ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1) by Ali G Turhan Affiliation

Pole de Biologie-Sante - 40 avenue du Recteur Pineau - 86022 Poitiers Cedex, France

1997-10-01 ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1) by Jean-Loup Huret Affiliation

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France