Biology:Anaplastic lymphoma kinase

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][2]

Identification

Anaplastic lymphoma kinase (ALK) was originally discovered in 1994[1][3] in anaplastic large-cell lymphoma (ALCL) cells. ALCL is caused by a (2;5)(p23:q35) chromosomal translocation that generates the fusion protein NPM-ALK, in which the kinase domain of ALK is fused to the amino-terminal part of the nucleophosmin (NPM) protein. Dimerization of NPM constitutively activates the ALK kinase domain.[1][3]

The full-length protein ALK was identified in 1997 by two groups.[4][5] The deduced amino acid sequences revealed that ALK was a novel receptor tyrosine kinase (RTK), having an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain.[4][5] While the tyrosine kinase domain of human ALK shares a high degree of similarity with that of the insulin receptor, its extracellular domain is unique among the RTK family in containing two MAM domains (meprin, A5 protein and receptor protein tyrosine phosphatase mu), an LDLa domain (low-density lipoprotein receptor class A) and a glycine-rich region.[5][6] Based on overall homology, ALK is closely related to the leukocyte receptor tyrosine kinase (LTK) and, together with the insulin receptor, forms a subgroup in the RTK superfamily.[4][5] The human ALK gene encodes a protein 1,620 amino acids long with a molecular weight of 180 kDa.[4][5]

Since the original discovery of the receptor in mammals, several orthologs of ALK have been identified: dAlk in the fruit fly (Drosophila melanogaster) in 2001,[6] scd-2 in the nematode (Caenorhabditis elegans) in 2004,[7] and DrAlk in the zebrafish (Danio rerio) in 2013.[8]

The ligands of the human ALK/LTK receptors were identified in 2014:[9][10][11] FAM150A (AUGβ) and FAM150B (AUGα), two small secreted peptides that strongly activate ALK signaling. In invertebrates, ALK-activating ligands are Jelly belly (Jeb) in Drosophila,[12][13] and hesitation behaviour 1 (HEN-1) in C. elegans.[14] No such ligands have been reported yet in zebrafish or other vertebrates.[15]

Mechanism

Following binding of the ligand, the full-length receptor ALK dimerizes, changes conformation, and autoactivates its own kinase domain, which in turn phosphorylates other ALK receptors in trans on specific tyrosine amino acid residues. ALK phosphorylated residues serve as binding sites for the recruitment of several adaptor and other cellular proteins, such as GRB2,[16] IRS1,[16][17] Shc,[16][18] Src,[19] FRS2,[18] PTPN11/Shp2,[20] PLCγ,[21][17] PI3K,[22][17] and NF1.[23] Other reported downstream ALK targets include FOXO3a,[24] CDKN1B/p27kip,[25] cyclin D2, NIPA,[26][27] RAC1,[28] CDC42,[29] p130CAS,[30] SHP1,[31] and PIKFYVE.[32]

Phosphorylated ALK activates multiple downstream signal transduction pathways, including MAPK-ERK, PI3K-AKT, PLCγ, CRKL-C3G, and JAK-STAT.[33][15]

Function

The receptor ALK plays a pivotal role in cellular communication and in the normal development and function of the nervous system.[2] This observation is based on the extensive expression of ALK messenger RNA (mRNA) throughout the nervous system during mouse embryogenesis.[4][5][34] In vitro functional studies have demonstrated that ALK activation promotes neuronal differentiation of PC12[35][36][37][18] or neuroblastoma cell lines.[17]

ALK is critical for embryonic development in Drosophila. Flies lacking the receptor die due to failure of founder cell specification in embryonic visceral muscle.[12][13][38] However, while ALK knockout mice exhibit defects in neurogenesis and testosterone production, they remain viable, suggesting that ALK is not critical to their developmental processes.[39][40][41]

ALK regulates retinal axon targeting,[42] growth and size,[23][43] synapse development[7] at the neuromuscular junction,[44][45] behavioral responses to ethanol,[46][47][48][49] and sleep.[50] It restricts and constrains learning and long-term memory[23][51][40] and small-molecule inhibitors of the ALK receptor can improve learning,[23] long-term memory,[51] and extend healthy lifespan.[52] ALK is also a candidate thinness gene, as its genetic deletion leads to resistance to diet- and leptin-mutation-induced obesity.[53][N 1]

Pathology

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.[33][15]

Anaplastic large-cell lymphoma

The 2;5 chromosomal translocation is associated with approximately 60% of anaplastic large-cell lymphomas (ALCLs), type ALK-positive anaplastic large cell lymphoma and very rare cases of ALCL type primary cutaneous anaplastic large cell lymphoma. 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.[54]

Adenocarcinoma of the lung

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.[55] Patients with this ALK rearrangement have the following clinicopathologic characteristics: Young age at diagnosis (median 50 years), female gender, nonsmoker/light smoker, adenocarcinoma histology with specific morphologic patterns such as cribriform and solid signet ring, expression of thyroid transcription factor 1, tendency to metastasize to pleura or pericardium, frequently with more metastases than other molecular types, and predominantly metastases to the central nervous system.[56] The standard test used to detect this gene in tumor samples is fluorescence in situ hybridization (FISH) by a US FDA approved kit. Recently Roche Ventana obtained approval in China and European Union countries to test this mutation by immunohistochemistry.[55] Other techniques like reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion but not recommended.[citation needed] ALK lung cancers are found in patients of all ages, although on average these patients tend to be 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. EML4-ALK-rearrangement in NSCLC is exclusive and not found in EGFR- or KRAS-mutated tumors.[57]

Gene rearrangements and overexpression in other tumours

ALK inhibitors

Main page: Chemistry:ALK inhibitor
  • Xalkori (crizotinib), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.[72] 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%.

In patients affected by relapsed or refractory ALK+ Anaplastic Large Cell Lymphoma, crizotinib produced objective response rates ranging from 65% to 90% and 3 year progression free survival rates of 60-75%. No relapse of the lymphoma was ever observed after the initial 100 days of treatment. Treatment must be continued indefinitely at present.[73][74][75]

  • Ceritinib was approved by the FDA in April 2014 for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.[76]
  • Entrectinib (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the three NTRK genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. An open label, multicenter, global phase 2 clinical trial called STARTRK-2 is currently underway to test the drug in patients with ROS1/NTRK/ALK gene rearrangements.

See also

Notes and references

Notes

  1. ↑ In 2020, a genome-wide association study (GWAS) was published of 47,102 people in the Estonian Genome Center of the University of Tartu (EGCUT) Biobank which compared the DNA of healthy thin individuals in the lowest 6th percentile of body mass index to the DNA of normal-weight individuals. This study identified a number of genetic variations of the ALK gene that were associated with thinness. As a next step, experiments in mice and Drosophila fruit flies showed that mice in which the ALK gene was knocked out had the similar activity and diet levels as normal mice, but had lower body fat and weight from early age into adulthood. This implies that inhibition of this kinase, already of interest as a chemotherapy for cancers associated with this gene, might be a way to prevent weight gain.

References

  1. ↑ 1.0 1.1 1.2 "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Science 263 (5151): 1281–1284. March 1994. doi:10.1126/science.8122112. PMID 8122112. Bibcode: 1994Sci...263.1281M. 
  2. ↑ 2.0 2.1 "Entrez Gene: ALK anaplastic lymphoma kinase (Ki-1)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=238. 
  3. ↑ 3.0 3.1 "Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3". Oncogene 9 (6): 1567–1574. June 1994. PMID 8183550. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system". Oncogene 14 (4): 439–449. January 1997. doi:10.1038/sj.onc.1200849. PMID 9053841. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "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): 2175–2188. May 1997. doi:10.1038/sj.onc.1201062. PMID 9174053. 
  6. ↑ 6.0 6.1 "Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo". Genes to Cells 6 (6): 531–544. June 2001. doi:10.1046/j.1365-2443.2001.00440.x. PMID 11442633. 
  7. ↑ 7.0 7.1 "An SCF-like ubiquitin ligase complex that controls presynaptic differentiation". Nature 430 (6997): 345–350. July 2004. doi:10.1038/nature02647. PMID 15208641. Bibcode: 2004Natur.430..345L. 
  8. ↑ "Anaplastic lymphoma kinase is required for neurogenesis in the developing central nervous system of zebrafish". PLOS ONE 8 (5): e63757. May 2013. doi:10.1371/journal.pone.0063757. PMID 23667670. Bibcode: 2013PLoSO...863757Y. 
  9. ↑ "FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase". eLife 4: e09811. September 2015. doi:10.7554/eLife.09811. PMID 26418745. 
  10. ↑ "Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand-receptor interactions". Proceedings of the National Academy of Sciences of the United States of America 112 (52): 15862–15867. December 2015. doi:10.1073/pnas.1520099112. PMID 26630010. Bibcode: 2015PNAS..11215862R. 
  11. ↑ "Deorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a signaling screen of the extracellular proteome". Proceedings of the National Academy of Sciences of the United States of America 111 (44): 15741–15745. November 2014. doi:10.1073/pnas.1412009111. PMID 25331893. Bibcode: 2014PNAS..11115741Z. 
  12. ↑ 12.0 12.1 "Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion". Nature 425 (6957): 512–516. October 2003. doi:10.1038/nature01950. PMID 14523447. Bibcode: 2003Natur.425..512E. 
  13. ↑ 13.0 13.1 "Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers". Nature 425 (6957): 507–512. October 2003. doi:10.1038/nature01916. PMID 14523446. Bibcode: 2003Natur.425..507L. 
  14. ↑ "C. elegans anaplastic lymphoma kinase ortholog SCD-2 controls dauer formation by modulating TGF-beta signaling". Current Biology 18 (15): 1101–1109. August 2008. doi:10.1016/j.cub.2008.06.060. PMID 18674914. 
  15. ↑ 15.0 15.1 15.2 "Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology". Nature Reviews. Cancer 13 (10): 685–700. October 2013. doi:10.1038/nrc3580. PMID 24060861. 
  16. ↑ 16.0 16.1 16.2 "Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5)". Proceedings of the National Academy of Sciences of the United States of America 93 (9): 4181–4186. April 1996. doi:10.1073/pnas.93.9.4181. PMID 8633037. Bibcode: 1996PNAS...93.4181F. 
  17. ↑ 17.0 17.1 17.2 17.3 "ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth". Journal of Cell Science 117 (Pt 15): 3319–3329. July 2004. doi:10.1242/jcs.01183. PMID 15226403. 
  18. ↑ 18.0 18.1 18.2 "ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation". FEBS Letters 581 (4): 727–734. February 2007. doi:10.1016/j.febslet.2007.01.039. PMID 17274988. 
  19. ↑ "Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity". Blood 103 (4): 1464–1471. February 2004. doi:10.1182/blood-2003-04-1038. PMID 14563642. 
  20. ↑ "The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration". Cancer Research 67 (9): 4278–4286. May 2007. doi:10.1158/0008-5472.CAN-06-4350. PMID 17483340. 
  21. ↑ "Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity". Molecular and Cellular Biology 18 (12): 6951–6961. December 1998. doi:10.1128/mcb.18.12.6951. PMID 9819383. 
  22. ↑ "Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway". Blood 96 (13): 4319–4327. December 2000. doi:10.1182/blood.v96.13.4319.h8004319_4319_4327. PMID 11110708. 
  23. ↑ 23.0 23.1 23.2 23.3 "The receptor tyrosine kinase Alk controls neurofibromin functions in Drosophila growth and learning". PLOS Genetics 7 (9): e1002281. September 2011. doi:10.1371/journal.pgen.1002281. PMID 21949657. 
  24. ↑ "NPM-ALK fusion kinase of anaplastic large-cell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a". Blood 103 (12): 4622–4629. June 2004. doi:10.1182/blood-2003-03-0820. PMID 14962911. 
  25. ↑ "Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma". Blood 105 (2): 827–829. January 2005. doi:10.1182/blood-2004-06-2125. PMID 15374880. 
  26. ↑ "Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA)". The Journal of Biological Chemistry 278 (32): 30028–30036. August 2003. doi:10.1074/jbc.M300883200. PMID 12748172. 
  27. ↑ "NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry". Cell 122 (1): 45–57. July 2005. doi:10.1016/j.cell.2005.04.034. PMID 16009132. 
  28. ↑ "Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas". Oncogene 27 (19): 2728–2736. April 2008. doi:10.1038/sj.onc.1210921. PMID 17998938. 
  29. ↑ "The anaplastic lymphoma kinase controls cell shape and growth of anaplastic large cell lymphoma through Cdc42 activation". Cancer Research 68 (21): 8899–8907. November 2008. doi:10.1158/0008-5472.CAN-08-2568. PMID 18974134. 
  30. ↑ "p130Cas mediates the transforming properties of the anaplastic lymphoma kinase". Blood 106 (12): 3907–3916. December 2005. doi:10.1182/blood-2005-03-1204. PMID 16105984. 
  31. ↑ "The tyrosine 343 residue of nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) is important for its interaction with SHP1, a cytoplasmic tyrosine phosphatase with tumor suppressor functions". The Journal of Biological Chemistry 285 (26): 19813–19820. June 2010. doi:10.1074/jbc.M110.121988. PMID 20424160. 
  32. ↑ "The nucleophosmin-anaplastic lymphoma kinase oncogene interacts, activates, and uses the kinase PIKfyve to increase invasiveness". The Journal of Biological Chemistry 286 (37): 32105–32114. September 2011. doi:10.1074/jbc.M111.227512. PMID 21737449. 
  33. ↑ 33.0 33.1 "Anaplastic lymphoma kinase: signalling in development and disease". The Biochemical Journal 420 (3): 345–361. May 2009. doi:10.1042/BJ20090387. PMID 19459784. 
  34. ↑ "Characterization of the expression of the ALK receptor tyrosine kinase in mice". Gene Expression Patterns 6 (5): 448–461. June 2006. doi:10.1016/j.modgep.2005.11.006. PMID 16458083. 
  35. ↑ "Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway". The Journal of Biological Chemistry 276 (12): 9526–9531. March 2001. doi:10.1074/jbc.M007333200. PMID 11121404. 
  36. ↑ "Activation and inhibition of anaplastic lymphoma kinase receptor tyrosine kinase by monoclonal antibodies and absence of agonist activity of pleiotrophin". The Journal of Biological Chemistry 280 (28): 26039–26048. July 2005. doi:10.1074/jbc.M501972200. PMID 15886198. 
  37. ↑ "Role of the subcellular localization of ALK tyrosine kinase domain in neuronal differentiation of PC12 cells". Journal of Cell Science 118 (Pt 24): 5811–5823. December 2005. doi:10.1242/jcs.02695. PMID 16317043. 
  38. ↑ "Myoblast determination in the somatic and visceral mesoderm depends on Notch signalling as well as on milliways(mili(Alk)) as receptor for Jeb signalling". Development 131 (4): 743–754. February 2004. doi:10.1242/dev.00972. PMID 14757637. 
  39. ↑ "Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications". Neuropsychopharmacology 33 (3): 685–700. February 2008. doi:10.1038/sj.npp.1301446. PMID 17487225. 
  40. ↑ 40.0 40.1 "Anaplastic lymphoma kinase and leukocyte tyrosine kinase: functions and genetic interactions in learning, memory and adult neurogenesis". Pharmacology, Biochemistry, and Behavior 100 (3): 566–574. January 2012. doi:10.1016/j.pbb.2011.10.024. PMID 22079349. 
  41. ↑ "Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism". PLOS ONE 10 (5): e0123542. May 2015. doi:10.1371/journal.pone.0123542. PMID 25955180. Bibcode: 2015PLoSO..1023542W. 
  42. ↑ "Anterograde Jelly belly and Alk receptor tyrosine kinase signaling mediates retinal axon targeting in Drosophila". Cell 128 (5): 961–975. March 2007. doi:10.1016/j.cell.2007.02.024. PMID 17350579. 
  43. ↑ "Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila". Cell 146 (3): 435–447. August 2011. doi:10.1016/j.cell.2011.06.040. PMID 21816278. 
  44. ↑ "Anterograde Jelly belly ligand to Alk receptor signaling at developing synapses is regulated by Mind the gap". Development 137 (20): 3523–3533. October 2010. doi:10.1242/dev.047878. PMID 20876658. 
  45. ↑ "Jelly Belly trans-synaptic signaling to anaplastic lymphoma kinase regulates neurotransmission strength and synapse architecture". Developmental Neurobiology 73 (3): 189–208. March 2013. doi:10.1002/dneu.22056. PMID 22949158. 
  46. ↑ "An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol". PLOS ONE 6 (7): e22636. Jul 2011. doi:10.1371/journal.pone.0022636. PMID 21799923. Bibcode: 2011PLoSO...622636L. 
  47. ↑ "Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice". Neuropharmacology 107: 1–8. August 2016. doi:10.1016/j.neuropharm.2016.03.003. PMID 26946429. 
  48. ↑ "Anaplastic lymphoma kinase regulates binge-like drinking and dopamine receptor sensitivity in the ventral tegmental area". Addiction Biology 22 (3): 665–678. May 2017. doi:10.1111/adb.12358. PMID 26752591. 
  49. ↑ "Anaplastic Lymphoma Kinase Is a Regulator of Alcohol Consumption and Excitatory Synaptic Plasticity in the Nucleus Accumbens Shell". Frontiers in Pharmacology 8: 533. Aug 2017. doi:10.3389/fphar.2017.00533. PMID 28860990. 
  50. ↑ "Anaplastic Lymphoma Kinase Acts in the Drosophila Mushroom Body to Negatively Regulate Sleep". PLOS Genetics 11 (11): e1005611. November 2015. doi:10.1371/journal.pgen.1005611. PMID 26536237. 
  51. ↑ 51.0 51.1 "The Drosophila Receptor Tyrosine Kinase Alk Constrains Long-Term Memory Formation". The Journal of Neuroscience 38 (35): 7701–7712. August 2018. doi:10.1523/JNEUROSCI.0784-18.2018. PMID 30030398. 
  52. ↑ "The neuronal receptor tyrosine kinase Alk is a target for longevity". Aging Cell 19 (5): e13137. May 2020. doi:10.1111/acel.13137. PMID 32291952. 
  53. ↑ "Identification of ALK in Thinness". Cell 181 (6): 1246–1262.e22. June 2020. doi:10.1016/j.cell.2020.04.034. PMID 32442405. 
  54. ↑ "Inhibitors of the anaplastic lymphoma kinase". Expert Opinion on Investigational Drugs 21 (7): 985–994. July 2012. doi:10.1517/13543784.2012.690031. PMID 22612599. 
  55. ↑ 55.0 55.1 "VENTANA ALK (D5F3) CDx Assay". https://diagnostics.roche.com/us/en/products/tests/ventana-alk-_d5f3-cdx-assay0.html. 
  56. ↑ "An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance". Bosnian Journal of Basic Medical Sciences 22 (1): 1–13. February 2022. doi:10.17305/bjbms.2021.5859. PMID 34082691. 
  57. ↑ "International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma". Journal of Thoracic Oncology 6 (2): 244–285. February 2011. doi:10.1097/JTO.0b013e318206a221. PMID 21252716. 
  58. ↑ "Identification of ALK as a major familial neuroblastoma predisposition gene". Nature 455 (7215): 930–935. October 2008. doi:10.1038/nature07261. PMID 18724359. Bibcode: 2008Natur.455..930M. 
  59. ↑ "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): 354–362. August 2002. doi:10.1002/gcc.10033. PMID 12112524. 
  60. ↑ "TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors". The American Journal of Pathology 157 (2): 377–384. August 2000. doi:10.1016/S0002-9440(10)64550-6. PMID 10934142. 
  61. ↑ "ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients". Modern Pathology 25 (11): 1516–1525. November 2012. doi:10.1038/modpathol.2012.107. PMID 22743654. 
  62. ↑ "Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method". Cancer 118 (18): 4427–4436. September 2012. doi:10.1002/cncr.27391. PMID 22252991. 
  63. ↑ "Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum". Modern Pathology 24 (3): 430–442. March 2011. doi:10.1038/modpathol.2010.213. PMID 21076462. 
  64. ↑ "ALK rearrangement in sickle cell trait-associated renal medullary carcinoma". Genes, Chromosomes & Cancer 50 (3): 146–153. March 2011. doi:10.1002/gcc.20839. PMID 21213368. 
  65. ↑ "Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer". World Journal of Gastroenterology 12 (44): 7104–7112. November 2006. doi:10.3748/wjg.v12.i44.7104. PMID 17131471. 
  66. ↑ "Primary oesophageal Ki (CD30)-positive ALK+ anaplastic large cell lymphoma of T-cell phenotype". Singapore Medical Journal 49 (10): e289–e292. October 2008. PMID 18946602. 
  67. ↑ 67.0 67.1 "Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers". Molecular Cancer Research 7 (9): 1466–1476. September 2009. doi:10.1158/1541-7786.MCR-08-0522. PMID 19737969. 
  68. ↑ "ALK gene amplified in most inflammatory breast cancers". Journal of the National Cancer Institute 104 (2): 87–88. January 2012. doi:10.1093/jnci/djr553. PMID 22215853. 
  69. ↑ "Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth". The Journal of Biological Chemistry 277 (16): 14153–14158. April 2002. doi:10.1074/jbc.M112354200. PMID 11809760. 
  70. ↑ "Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin". The Journal of Biological Chemistry 276 (20): 16772–16779. May 2001. doi:10.1074/jbc.M010660200. PMID 11278720. 
  71. ↑ "Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene". Cancer Research 71 (13): 4403–4411. July 2011. doi:10.1158/0008-5472.CAN-10-4041. PMID 21596819. 
  72. ↑ "Xalkori Approved for Lung Cancer". FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. 
  73. ↑ "Clinical activity of crizotinib in advanced, chemoresistant ALK+ lymphoma patients.". 2010 Annual Meeting of the American Society of Hematology. Orlando, Florida. 
  74. ↑ "Crizotinib in anaplastic large-cell lymphoma". The New England Journal of Medicine 364 (8): 775–776. February 2011. doi:10.1056/NEJMc1013224. PMID 21345110. 
  75. ↑ "Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients". Journal of the National Cancer Institute 106 (2): djt378. February 2014. doi:10.1093/jnci/djt378. PMID 24491302. 
  76. ↑ "ZYKADIA (ceritinib) capsules, for oral use Initial U.S. Approval: 2014". United States Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205755s000lbl.pdf. 

Further reading

External links

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