Anaplastic lymphoma kinase
From Wikipedia, the free encyclopedia
Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ALK gene.[2][3]
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Function [edit]
ALK plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system.[3]
The deduced amino acid sequences reveal that ALK is a novel receptor tyrosine kinase having a putative transmembrane domain and an extracellular domain. These sequences are absent in the product of the transforming NPM-ALK gene. ALK shows the greatest sequence similarity to LTK (leukocyte tyrosine kinase).
Pathology [edit]
The ALK gene can be oncogenic in three ways – by forming a fusion gene with any of several other genes, by gaining additional gene copies or with mutations of the actual DNA code for the gene itself.
Anaplastic large-cell lymphoma [edit]
The 2;5 chromosomal translocation is associated with approximately 60% anaplastic large-cell lymphomas (ALCLs). The translocation creates a fusion gene consisting of the ALK (anaplastic lymphoma kinase) gene and the nucleophosmin (NPM) gene: the 3' half of ALK, derived from chromosome 2 and coding for the catalytic domain, is fused to the 5' portion of NPM from chromosome 5. The product of the NPM-ALK fusion gene is oncogenic. In a smaller fraction of ALCL patients, the 3' half of ALK is fused to the 5' sequence of TPM3 gene, encoding for tropomyosin 3. In rare cases, ALK is fused to other 5' fusion partners, such as TFG, ATIC, CLTC1, TPM4, MSN, ALO17, MYH9.[4]
Non-small-cell lung cancer [edit]
The EML4-ALK fusion gene is responsible for approximately 3-5% of non-small-cell lung cancer(NSCLC). The vast majority of cases are adenocarcinomas. The standard test used to detect this gene in tumor samples is fluorescence in situ hybridization (FISH), but other techniques such as immunohistochemistry (IHC) and reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion. ALK lung cancers are found in patients of all ages, although on average these patients may be somewhat younger. ALK lung cancers are more common in light cigarette smokers or nonsmokers, but a significant number of patients with this disease are current or former cigarette smokers.
Gene rearrangements and overexpression in other tumours [edit]
- Familial cases of neuroblastoma[5]
- Inflammatory myofibroblastic tumor[6][7]
- Adult[8][9] and pediatric[10][11] renal cell carcinomas
- Esophageal squamous cell carcinoma[12][13]
- Breast cancer,[14] notably the inflammatory subtype[15]
- Colonic adenocarcinoma[14]
- Glioblastoma multiforme[16][17]
- Anaplastic thyroid cancer[18]
ALK inhibitors [edit]
Main article: ALK inhibitor
Xalkori (crizotinib), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.[19] Early results of an initial Phase I trial with 82 patients with ALK induced lung cancer showed an overall response rate of 57%, a disease control rate at 8 weeks of 87% and progression free survival at 6 months of 72%.
See also [edit]
References [edit]
- ^ Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP (September 2011). "Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)". J. Med. Chem. 54 (18): 6342–63. doi:10.1021/jm2007613. PMID 21812414.
- ^ Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT (Apr 1994). "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Science 263 (5151): 1281–4. doi:10.1126/science.8122112. PMID 8122112.
- ^ a b "Entrez Gene: ALK anaplastic lymphoma kinase (Ki-1)".
- ^ Mologni L (July 2012). "Inhibitors of the anaplastic lymphoma kinase". Expert Opin Investig Drugs 21 (7): 985–94. doi:10.1517/13543784.2012.690031. PMID 22612599.
- ^ Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM (October 2008). "Identification of ALK as a major familial neuroblastoma predisposition gene". Nature 455 (7215): 930–5. doi:10.1038/nature07261. PMC 2672043. PMID 18724359. Lay summary – PRNewswire-USNewswire.
- ^ Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, Marynen P (August 2002). "Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor". Genes Chromosomes Cancer 34 (4): 354–62. doi:10.1002/gcc.10033. PMID 12112524.
- ^ Lawrence B, Perez-Atayde A, Hibbard MK, Rubin BP, Dal Cin P, Pinkus JL, Pinkus GS, Xiao S, Yi ES, Fletcher CD, Fletcher JA (August 2000). "TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors". Am. J. Pathol. 157 (2): 377–84. doi:10.1016/S0002-9440(10)64550-6. PMC 1850130. PMID 10934142.
- ^ Sukov WR, Hodge JC, Lohse CM, Akre MK, Leibovich BC, Thompson RH, Cheville JC (November 2012). "ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients". Mod. Pathol. 25 (11): 1516–25. doi:10.1038/modpathol.2012.107. PMID 22743654.
- ^ Sugawara E, Togashi Y, Kuroda N, Sakata S, Hatano S, Asaka R, Yuasa T, Yonese J, Kitagawa M, Mano H, Ishikawa Y, Takeuchi K (September 2012). "Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method". Cancer 118 (18): 4427–36. doi:10.1002/cncr.27391. PMID 22252991.
- ^ Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, Bridge JA (March 2011). "Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum". Mod. Pathol. 24 (3): 430–42. doi:10.1038/modpathol.2010.213. PMID 21076462.
- ^ Mariño-Enríquez A, Ou WB, Weldon CB, Fletcher JA, Pérez-Atayde AR (March 2011). "ALK rearrangement in sickle cell trait-associated renal medullary carcinoma". Genes Chromosomes Cancer 50 (3): 146–53. doi:10.1002/gcc.20839. PMID 21213368.
- ^ Jazii FR, Najafi Z, Malekzadeh R, Conrads TP, Ziaee AA, Abnet C, Yazdznbod M, Karkhane AA, Salekdeh GH (November 2006). "Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer". World J. Gastroenterol. 12 (44): 7104–12. PMID 17131471.
- ^ Yaakup H, Sagap I, Fadilah SA (October 2008). "Primary oesophageal Ki (CD30)-positive ALK+ anaplastic large cell lymphoma of T-cell phenotype". Singapore Med J 49 (10): e289–92. PMID 18946602.
- ^ a b Lin E, Li L, Guan Y, Soriano R, Rivers CS, Mohan S, Pandita A, Tang J, Modrusan Z (September 2009). "Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers". Mol. Cancer Res. 7 (9): 1466–76. doi:10.1158/1541-7786.MCR-08-0522. PMID 19737969.
- ^ Tuma RS (January 2012). "ALK gene amplified in most inflammatory breast cancers". J. Natl. Cancer Inst. 104 (2): 87–8. doi:10.1093/jnci/djr553. PMID 22215853.
- ^ Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A (April 2002). "Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth". J. Biol. Chem. 277 (16): 14153–8. doi:10.1074/jbc.M112354200. PMID 11809760.
- ^ Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, Caughey DJ, Wen D, Karavanov A, Riegel AT, Wellstein A (May 2001). "Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin". J. Biol. Chem. 276 (20): 16772–9. doi:10.1074/jbc.M010660200. PMID 11278720.
- ^ Murugan AK, Xing M (July 2011). "Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene". Cancer Res. 71 (13): 4403–11. doi:10.1158/0008-5472.CAN-10-4041. PMC 3129369. PMID 21596819.
- ^ "Xalkori Approved for Lung Cancer". FDA.
Further reading [edit]
- Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ, Haralambieva E, Pulford K, Pileri S, Morris SW, Mason DY, Delsol G (March 1998). "ALK-positive lymphoma: a single disease with a broad spectrum of morphology". Blood 91 (6): 2076–84. PMID 9490693.
- Pulford K, Lamant L, Espinos E, Jiang Q, Xue L, Turturro F, Delsol G, Morris SW (December 2004). "The emerging normal and disease-related roles of anaplastic lymphoma kinase". Cell. Mol. Life Sci. 61 (23): 2939–53. doi:10.1007/s00018-004-4275-9. PMID 15583856.
- Fujimoto J, Shiota M, Iwahara T, Seki N, Satoh H, Mori S, Yamamoto T (April 1996). "Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5)". Proc. Natl. Acad. Sci. U.S.A. 93 (9): 4181–6. doi:10.1073/pnas.93.9.4181. PMC 39508. PMID 8633037.
- Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T (January 1997). "Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system". Oncogene 14 (4): 439–49. doi:10.1038/sj.onc.1200849. PMID 9053841.
- Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X, Witte DP (May 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)". Oncogene 14 (18): 2175–88. doi:10.1038/sj.onc.1201062. PMID 9174053.
- Bai RY, Dieter P, Peschel C, Morris SW, Duyster J (December 1998). "Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity". Mol. Cell. Biol. 18 (12): 6951–61. PMC 109278. PMID 9819383.
- Hernández L, Pinyol M, Hernández S, et al. (1999). "TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations". Blood 94 (9): 3265–8. PMID 10556217.
- Souttou B, Carvalho NB, Raulais D, Vigny M (March 2001). "Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway". J. Biol. Chem. 276 (12): 9526–31. doi:10.1074/jbc.M007333200. PMID 11121404.
- Simonitsch I, Polgar D, Hajek M, Duchek P, Skrzypek B, Fassl S, Lamprecht A, Schmidt G, Krupitza G, Cerni C (June 2001). "The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation". FASEB J. 15 (8): 1416–8. PMID 11387242.
- Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M, Levy DE, Inghirami G (February 2002). "Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death". Oncogene 21 (7): 1038–47. doi:10.1038/sj.onc.1205152. PMID 11850821.
- Passoni L, Scardino A, Bertazzoli C, Gallo B, Coluccia AM, Lemonnier FA, Kosmatopoulos K, Gambacorti-Passerini C (March 2002). "ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes". Blood 99 (6): 2100–6. doi:10.1182/blood.V99.6.2100. PMID 11877285.
- Bonvini P, Gastaldi T, Falini B, Rosolen A (March 2002). "Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin". Cancer Res. 62 (5): 1559–66. PMID 11888936.
- Hernández L, Beà S, Bellosillo B, Pinyol M, Falini B, Carbone A, Ott G, Rosenwald A, Fernández A, Pulford K, Mason D, Morris SW, Santos E, Campo E (April 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". Am. J. Pathol. 160 (4): 1487–94. doi:10.1016/S0002-9440(10)62574-6. PMC 1867210. PMID 11943732.
- ten Berge RL, Meijer CJ, Dukers DF, Kummer JA, Bladergroen BA, Vos W, Hack CE, Ossenkoppele GJ, Oudejans JJ (June 2002). "Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma". Blood 99 (12): 4540–6. doi:10.1182/blood.V99.12.4540. PMID 12036886.
- Dirks WG, Fähnrich S, Lis Y, Becker E, MacLeod RA, Drexler HG (July 2002). "Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines". Int. J. Cancer 100 (1): 49–56. doi:10.1002/ijc.10435. PMID 12115586.
External links [edit]
- ALK protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
- ALK Correlations, Experiments, Publications and Clinical Trials
- GeneReviews/NCBI/NIH/UW entry on ALK-Related Neuroblastoma Susceptibility
- OMIM entries on ALK-Related Neuroblastoma Susceptibility
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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