ALK (anaplastic lymphoma receptor tyrosine kinase)

2010-02-01 Michèle Allouche Affiliation

Identity

HGNC

ALK

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

238

ALIAS

CD246,NBLST3

FUSION GENES

Show Gene Fusions

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).

Homology

Homologies with the insulin receptor super family: LTK (leucocyte tyrosine kinase), IGF1-R, IRb, TRKA, ROS (homolog of the drosophila Sevenless).

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.

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

Either t(X;2)(q11;p23), t(1;2)(q25;p23), inv(2)(p23q35), t(2;3)(p23;q21), t(2;17)(p23;q23), t(2;17)(p23;q25), t(2;19)(p23;p13.1) or t(2;22)(p23;q11.2).

Hybrid gene

5 MSN, TPM3, ATIC, TFG, CLTC, ALO17, TPM4 or MYH9 - 3 ALK.

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

5 TPM3 in the t(1;2), RANBP2 in the t(2;2) or inv(2)(p23;q11-13), 5 ATIC in inv(2)(p23;q35), 5 SEC31L1 in t(2;4), 5 CARS in the t(2;11), 5 CLTC in the t(2;17), or 5 TPM4 in the t(2;19) - 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+ 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

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

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).

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.

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.

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

Gene ID	Transcript ID	Uniprot
ENSG00000171094	ENST00000389048	Q9UM73
ENSG00000171094	ENST00000431873	E7EPW7
ENSG00000171094	ENST00000453137	H7BZ33
ENSG00000171094	ENST00000618119	A0A087WZL3
ENSG00000171094	ENST00000642122	A0A0K2YUJ3

Expression (GTEx)

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
Non-small cell lung cancer	KEGG	ko05223
Non-small cell lung cancer	KEGG	hsa05223

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	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/alk-(anaplastic-lymphoma-receptor-tyrosine-kinase)

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