Identity
HGNC
LOCATION
2p23.2
IMAGE
LEGEND
ALK (2p23) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
IMAGE
LEGEND
ALK (anaplastic lymphoma receptor tyrosine kinase) Hybridization with Vysis ALK Break Apart probe (Abbott Molecular, US) showing the gene at 2p23 (red-green or a fused yellow signal - Courtesy Adriana Zamecnikova.
LOCUSID
ALIAS
CD246,NBLST3
FUSION GENES
DNA/RNA
Description
The gene is composed of 29 exons spanning in a region of 728793 bp.
Transcription
6226 bp cDNA; coding sequence: 4.9 kb.
Proteins
Description
1620 amino acids; 177 kDa; after glycosylation, produces a 200 kDa mature glycoprotein; type I transmembrane receptor; composed of an extracellular region (containing two MAM and one LDLa domains, and one glycin-rich region), a transmembrane, and an intracellular region (composed of a juxta-membrane domain, a tyrosine kinase domain (1122-1376), and a C-terminal domain; dimerization.
Expression
Is tissue specific; mainly in: central and peripheral nervous system during development (less in adult), and testis; not in the lymphocytes.
Localisation
Cell membrane.
Function
ALK is a membrane associated tyrosine kinase receptor of the insulin receptor superfamily. The function of the full-length ALK receptor is poorly understood. It has a probable role in the central and peripheral nervous system development and maintenance. ALK is a dependence receptor, which may exert antagonist functions, proapoptotic or antiapoptotic, depending on the absence or presence of a ligand (Mourali et al., 2006). Dependence receptors have a potential role in cancer and development (Allouche, 2007). Ligands available for this demonstration were agonist anti-ALK antibodies (Motegi et al., 2004; Moog-Lutz et al., 2005). If a specific ALK ligand (jelly belly) has been clearly identified in Drosophila, it has no homologue in vertebrates (Palmer et al., 2009). ALK is still an orphan receptor, given the high level of controversy about pleiotrophin and midkine, which have been proposed as ligands by Stoica et al. (2001, 2002) (see review by Chiarle et al., 2008).
Implicated in
Entity name
ALK+ anaplastic large cell lymphoma (ALCL)
Disease
ALCL are high grade non Hodgkin lymphomas. ALK+ ALCL are ALCL where ALK is involved in a fusion gene; systemic ALK+ ALCL (as opposed to cutaneous ALCL, which are usually ALK negative) represent 60 to 80 % of ALCL cases (they are CD30+, ALK+); 70 to 80% of ALK+ ALCL cases bear a t(2;5); the remaining ALK+ ALCL cases bear variant translocations X-ALK, where X designates a partner gene.
Prognosis
Although presenting as a high grade tumour, an 80% five year survival is associated with this anomaly, but recurrence is a concern.
Cytogenetics
The prototype anomaly is the t(2;5)(p23;q35) generating the NPM1-ALK fusion.
Alternative anomalies involving the ALK gene in ALCL are described below as cytoplasmic ALK+ ALCL cases, among which the t(1;2) TPM3-ALK is found in 20% of ALK+ ALCL.
Complex karyotypes may also be found.
Alternative anomalies involving the ALK gene in ALCL are described below as cytoplasmic ALK+ ALCL cases, among which the t(1;2) TPM3-ALK is found in 20% of ALK+ ALCL.
Complex karyotypes may also be found.
Hybrid gene
5 NPM1 - 3 ALK on the der(5).
Fusion protein
680 amino acids, 80 kDa; N-term 117 amino acids from NPM1 fused to the 563 C-term amino acids of ALK (i.e. composed of the oligomerization domain and the metal binding site of NPM1, and the entire cytoplasmic portion of ALK); no apparent expression of the ALK/NPM1 counterpart. Characteristic localisation in the cytoplasm, nucleus and nucleolus, due to heterooligomerization of NPM1-ALK and normal NPM1 whereas the normal NPM1 protein is confined to the nucleus and nucleolus; constitutive activation of the catalytic domain of ALK.
Oncogenesis
Via the kinase function activated by oligomerization of NPM1-ALK mediated by the NPM1 part.
Entity name
Cytoplasmic ALK+ anaplasic large cell lymphoma (ALCL)
Prognosis
Present a favourable prognosis comparable to the one found in t(2;5) ALK+ ALCL.
Cytogenetics
Fusion protein
N-term amino acids from the partner gene fused to the 563 C-term amino acids (in the great majority of cases) from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); cytoplasmic/membraneous localisation only.
Oncogenesis
The partner gene seems to provoke the dimerization of the fused X-ALK, which should lead to constitutive autophosphorylation and activation of the ALK tyrosine kinase, as for NPM1-ALK (see t(2;5)(p23;q35)).
Entity name
Inflammatory myofibroblastic tumours with 2p23 rearrangements
Disease
Rare soft tissue tumour found in children and young adults about one third to half of inflammatory myofibroblastic tumour cases present with a 2p23 rearrangement involving ALK.
Prognosis
Good prognosis.
Cytogenetics
t(1;2)(q25;p23), t(2;2)(p23;q13) or inv(2)(p23;q11-13), inv(2)(p23;q35), t(2;4)(p23;q21), t(2;11)(p23;p15), t(2;17)(p23;q23), or t(2;19)(p23;p13.1) so far.
Hybrid gene
Fusion protein
N-term amino acids from the partner gene fused to the 563 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); homodimerization of the fusion protein is known or suspected.
Oncogenesis
Fused-ALK is constitutively activated.
Entity name
ALK+ diffuse large B-cell lymphoma (DLBCL)
Disease
Very rare form of DLBCL (40 cases described) expressing either ALK in fusion with CLTC (cytoplasmic granular localisation) associated to t(2;17)(p23;q23) (most frequently), or (rarely) NPM1-ALK in t(2;5)(p23;q35); tumours are EMA+, CD30- and CD20-negative.
Prognosis
Poor prognosis: aggressive lymphoma with 25% five year survival.
Cytogenetics
t(2;5)(p23;q35) or t(2;17)(p23;q23).
Hybrid gene
5 NPM1 or CLTC - 3 ALK.
Fusion protein
N-term amino acids from the partner gene fused to the 563 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); homodimerization of the fusion protein is known or suspected.
Oncogenesis
Fused-ALK is constitutively activated.
Entity name
ALK+ non-small cell lung cancer (NSCLC)
Disease
1-6 % of all NSCLC present a rearrangement involving ALK fused to EML4 in an inv(2)(p21p23); studies on East Asian and American/European patients (Soda et al., 2007; Perner et al., 2008).
Prognosis
50% survival at 24 months, so far (first identification in 2007).
Cytogenetics
inv(2)(p21;p23).
Hybrid gene
5 EML4 - 3 ALK; multiple variants of EML4-ALK noted depending on the breakpoint on the EML gene; ALK fusion starts at a portion encoded by exon 20.
Fusion protein
N-term amino acids from the partner gene fused to the 563 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); homodimerization of the fusion protein is known or suspected; protein is difficult to detect by classical immunohistochemistry methods (low expression).
Oncogenesis
Fused-ALK is constitutively activated.
Note: in a European study, EML4-ALK fusion transcript has also been found in up to 9% non-tumour lung tissue from lung tumour patients. Interestingly, the EML4-ALK transcript was not detected in matching tumour samples from the same patients (Martelli et al., 2009).
Note: in a European study, EML4-ALK fusion transcript has also been found in up to 9% non-tumour lung tissue from lung tumour patients. Interestingly, the EML4-ALK transcript was not detected in matching tumour samples from the same patients (Martelli et al., 2009).
Entity name
Familial neuroblastoma and sporadic neuroblastoma
Disease
Neuroblastoma is a cancer of early childhood that arises from the developing autonomic nervous system, giving rise to peripheral tumours. It is the most common malignancy diagnosed in the first year of life and shows a wide range of clinical phenotypes, with a few patients having tumours that regress spontaneously, whereas most patients have aggressive metastatic disease. It can be transmitted in an autosomal dominant mode as a familial predisposition, or occur as a sporadic disease.
Prognosis
Aggressive neuroblastoma cases have survival probabilities of less then 40% despite intensive chemoradiotherapy, and the disease continues to account for 15% of childhood cancer mortality.
Cytogenetics
Gene amplifications or mutations of ALK;
Associated alterations: tumours from patients with an aggressive phenotype often show amplification of the MYCN oncogene, and/or deletions of chromosome arms 1p and 11q.
Associated alterations: tumours from patients with an aggressive phenotype often show amplification of the MYCN oncogene, and/or deletions of chromosome arms 1p and 11q.
Hybrid gene
Several point mutations located in the coding region of the receptor intracellular portion, mostly in the tyrosine kinase domain.
Fusion protein
54 ALK mutations reported, affecting 12 different residues (Caren et al., 2008; Chen et al., 2008; George et al., 2008; Janoueix-Lerosey et al., 2008; Mosse et al., 2008); two hotspots: F1174 and R1275.
Most frequent germline mutations (familial cases): G1128A, R1192P, R1275Q.
Most frequent somatic mutations (sporadic cases): F1174L/I, F1245C/V.
Most frequent germline mutations (familial cases): G1128A, R1192P, R1275Q.
Most frequent somatic mutations (sporadic cases): F1174L/I, F1245C/V.
Oncogenesis
Gene amplifications or point mutations both confer constitutive kinase activation.
Breakpoints
Note
Most of the breakpoints occur in the same intron of ALK, whichever partner is involved in the fusion protein.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 17611412 | 2007 | ALK is a novel dependence receptor: potential implications in development and cancer. | Allouche M et al |
| 9121481 | 1997 | Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. | Bischof D et al |
| 11485898 | 2001 | Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor. | Bridge JA et al |
| 18923524 | 2008 | Oncogenic mutations of ALK kinase in neuroblastoma. | Chen Y et al |
| 18097461 | 2008 | The anaplastic lymphoma kinase in the pathogenesis of cancer. | Chiarle R et al |
| 10702393 | 2000 | ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35). | Colleoni GW et al |
| 12112524 | 2002 | Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. | Cools J et al |
| 13679433 | 2003 | Identification of CARS-ALK fusion in primary and metastatic lesions of an inflammatory myofibroblastic tumor. | Debelenko LV et al |
| 12115586 | 2002 | Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines. | Dirks WG et al |
| 10994999 | 2000 | Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. | Drexler HG et al |
| 11607814 | 2001 | Translocations involving anaplastic lymphoma kinase (ALK). | Duyster J et al |
| 12763927 | 2003 | ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. | Gascoyne RD et al |
| 18923525 | 2008 | Activating mutations in ALK provide a therapeutic target in neuroblastoma. | George RE et al |
| 10383129 | 1999 | Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. | Griffin CA et al |
| 11943732 | 2002 | Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: identification of a new TFG-ALK(XL) chimeric gene with transforming activity. | Hernández L et al |
| 9053841 | 1997 | Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. | Iwahara T et al |
| 20101209 | 2010 | Molecular pathogenesis of peripheral neuroblastic tumors. | Janoueix-Lerosey I et al |
| 10216106 | 1999 | A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation. | Lamant L et al |
| 12800156 | 2003 | Non-muscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma. | Lamant L et al |
| 8547653 | 1996 | High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining. | Lamant L et al |
| 10793082 | 2000 | Expression of the ALK tyrosine kinase gene in neuroblastoma. | Lamant L et al |
| 10934142 | 2000 | TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. | Lawrence B et al |
| 10706887 | 2000 | Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis. | Ma Z et al |
| 19032370 | 2008 | Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. | Mano H et al |
| 19147828 | 2009 | EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. | Martelli MP et al |
| 15886198 | 2005 | Activation and inhibition of anaplastic lymphoma kinase receptor tyrosine kinase by monoclonal antibodies and absence of agonist activity of pleiotrophin. | Moog-Lutz C et al |
| 8122112 | 1994 | Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. | Morris SW et al |
| 9174053 | 1997 | ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). | Morris SW et al |
| 18724359 | 2008 | Identification of ALK as a major familial neuroblastoma predisposition gene. | Mossé YP et al |
| 15226403 | 2004 | ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth. | Motegi A et al |
| 16880530 | 2006 | Anaplastic lymphoma kinase is a dependence receptor whose proapoptotic functions are activated by caspase cleavage. | Mourali J et al |
| 12816858 | 2003 | ALK-positive plasmablastic B-cell lymphoma with expression of the NPM-ALK fusion transcript: report of 2 cases. | Onciu M et al |
| 19459784 | 2009 | Anaplastic lymphoma kinase: signalling in development and disease. | Palmer RH et al |
| 16161041 | 2006 | Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor. | Panagopoulos I et al |
| 18320074 | 2008 | EML4-ALK fusion lung cancer: a rare acquired event. | Perner S et al |
| 15583856 | 2004 | The emerging normal and disease-related roles of anaplastic lymphoma kinase. | Pulford K et al |
| 7655022 | 1995 | Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: a distinct clinicopathologic entity. | Shiota M et al |
| 17625570 | 2007 | Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. | Soda M et al |
| 11090048 | 2000 | CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. | Stein H et al |
| 12122009 | 2002 | Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. | Stoica GE et al |
| 19383809 | 2009 | KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. | Takeuchi K et al |
| 11310834 | 2001 | Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. | Tort F et al |
| 10807789 | 2000 | Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like). | Touriol C et al |
| 10706082 | 2000 | A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma. | Trinei M et al |
| 15902287 | 2005 | What have we learnt from mouse models of NPM-ALK-induced lymphomagenesis? | Turner SD et al |
| 19275511 | 2009 | Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy. | Webb TR et al |
Other Information
Locus ID:
NCBI: 238
MIM: 105590
HGNC: 427
Ensembl: ENSG00000171094
Variants:
dbSNP: 238
ClinVar: 238
TCGA: ENSG00000171094
COSMIC: ALK
RNA/Proteins
Expression (GTEx)
Pathways
| Pathway | Source | External ID |
|---|---|---|
| Non-small cell lung cancer | KEGG | ko05223 |
| Non-small cell lung cancer | KEGG | hsa05223 |
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA165946122 | crizotinib | Chemical | LabelAnnotation, Literature, MultilinkAnnotation, VipGene | associated | 24433361, 25588040, 25945060 | ||
| PA165948903 | brentuximab vedotin | Chemical | LabelAnnotation | associated | |||
| PA166124615 | pembrolizumab | Chemical | LabelAnnotation | associated | |||
| PA166124616 | ceritinib | Chemical | LabelAnnotation, MultilinkAnnotation, VipGene | associated | 25945060, 26582431 | ||
| PA166129522 | nivolumab | Chemical | LabelAnnotation | associated | |||
| PA166129523 | atezolizumab | Chemical | LabelAnnotation | associated | |||
| PA166157522 | rs113488022 | Variant | LabelAnnotation | associated | |||
| PA166160050 | alectinib | Chemical | LabelAnnotation, VipGene | associated | 25588040 | ||
| PA166163482 | brigatinib | Chemical | LabelAnnotation, VipGene | associated | 25588040 | ||
| PA166182743 | lorlatinib | Chemical | LabelAnnotation | associated | |||
| PA166184558 | ramucirumab | Chemical | LabelAnnotation | associated | |||
| PA27769 | EML4 | Gene | MultilinkAnnotation | associated | 25706305 | ||
| PA443622 | Carcinoma, Non-Small-Cell Lung | Disease | MultilinkAnnotation, VipGene | associated | 25588040, 24091028, 25945060 | ||
| PA445100 | Neuroblastoma | Disease | MultilinkAnnotation, VipGene | associated | 24091028 | ||
| PA446541 | Lymphoma, Large-Cell, Anaplastic | Disease | VipGene | associated | 24091028 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37475109 | 2024 | Melanoma in infants, caused by a gene fusion involving the anaplastic lymphoma kinase (ALK). | 0 |
| 38000524 | 2024 | The acetylation of STAT3 at K685 attenuates NPM-ALK-induced tumorigenesis. | 0 |
| 38128254 | 2024 | Dissecting the role of ALK double mutations in drug resistance to lorlatinib with in-depth theoretical modeling and analysis. | 0 |
| 38307859 | 2024 | Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma. | 1 |
| 38451815 | 2024 | ALK upregulates POSTN and WNT signaling to drive neuroblastoma. | 0 |
| 37475109 | 2024 | Melanoma in infants, caused by a gene fusion involving the anaplastic lymphoma kinase (ALK). | 0 |
| 38000524 | 2024 | The acetylation of STAT3 at K685 attenuates NPM-ALK-induced tumorigenesis. | 0 |
| 38128254 | 2024 | Dissecting the role of ALK double mutations in drug resistance to lorlatinib with in-depth theoretical modeling and analysis. | 0 |
| 38307859 | 2024 | Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma. | 1 |
| 38451815 | 2024 | ALK upregulates POSTN and WNT signaling to drive neuroblastoma. | 0 |
| 32822792 | 2023 | Systemic juvenile xanthogranuloma has a higher frequency of ALK translocations than BRAFV600E mutations. | 7 |
| 35514136 | 2023 | Impact of compound mutations I1171N + F1174I and I1171N + L1198H on the structure of ALK in NSCLC pathogenesis: atomistic insights. | 2 |
| 35665929 | 2023 | New evidence of genetic heterogeneity causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes. | 2 |
| 36423218 | 2023 | Molecular characterization of genomic breakpoints of ALK rearrangements in non-small cell lung cancer. | 1 |
| 36720638 | 2023 | Functional consequence and therapeutic targeting of cryptic ALK fusions in monosomy 7 acute myeloid leukemia. | 1 |
Citation
Michèle Allouche
ALK (anaplastic lymphoma receptor tyrosine kinase)
Atlas Genet Cytogenet Oncol Haematol. 2010-02-01
Online version: http://atlasgeneticsoncology.org/gene/16
Historical Card
2003-08-01 ALK (anaplastic lymphoma receptor tyrosine kinase) by Jean-Loup Huret,Sylvie Senon Affiliation
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
2001-08-01 ALK (anaplastic lymphoma receptor tyrosine kinase) by Jean-Loup Huret Affiliation
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
1997-09-01 ALK (anaplastic lymphoma receptor tyrosine kinase) by Jean-Loup Huret Affiliation
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
