Ligand-independent dimerization of ALK fusions

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R-HSA-9700179
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Homo sapiens
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The ALK locus is subject to chromosomal translocations and inversions that give rise to oncogenic fusion proteins in a number of different cancers. To date, ALK has been identified as a fusion partner with more than 25 proteins in cancers ranging from anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), diffuse B-cell lymphoma, neuroblastoma, rhabdomyosarcoma and inflammatory myofibroblastic tumors, among others (reviewed in Roskoski, 2013; Della Corte et al, 2018). These fusion proteins form constitutive, ligand-independent dimers by virtue of an N-terminal dimerization domain contributed by the fusion partner, and retain the intracellular region of the ALK receptor tyrosine kinase. Expression (and often overexpression) of the fusion proteins is regulated by the promoter of the fusion partner. Signaling downstream of the fusion proteins occurs through numerous pathways including the MAP kinase, PI3K and STAT cascades, among others, but the extent to which each pathway is activated downstream of the different fusions varies (Armstrong et al, 2004; reviewed in Hallberg and Palmer, 2013; Hallberg and Palmer, 2016; Della Corte et al, 2018, Roskoski, 2013).
The best characterized ALK fusion protein is NPM-ALK, which occurs in 75-80% of ALCLs, and fuses the intracellular portion of ALK with the N-terminal region of nucleophosmin, a protein involved in DNA repair, transcription and genome stability. NPM-ALK constitutively dimerizes based on the N-terminal NPM region. Deletion of the N-terminal domain abrogates oligomerization and abolishes the transformation activity of the protein (Morris et al, 1995; Fujimoto et al, 1996).
In addition to NPM, fusions with ALK have also been identified with EML4 (Soda et al, 2007; Choi et al, 2008; Takezawa et al, 2011), CLTC (De Paepe et al, 2003; Cherchetti et al, 2011; Chiakatsu et al, 2003), TPM3 (Lamant et al, 1999; Lawrence et al, 2000), TPM4 (Lawrence et al, 2000), RANBP2 (Marino-Enriquez et al, 2011a; Lee et al, 2017; Chen et al, 2008), STRN (Majewska et al, 2013; Perot et al, 2014; Kelly et al, 2014), ATIC (Colleoni et al, 2000; Trinei et al, 2000; Ma et al, 2000), KIF5B (Wong et al, 2011), TFG (Hernandez et al, 1999; Hernandez et al, 2002), HIP1 (Ou et al, 2014; Hong et al, 2014; Fang et al, 2014), CARS1 (Cools et al, 2002; Debelenko et al, 2003), PPF1BP1 (Takeuchi et al, 2011; Yoshida et al, 2013), MSN (Tort et al, 2001), VCL (Marino-Enriquez et al, 2011b; Debelenko et al, 2011), KLC1 (Togayashi et al, 2012), SEC31A (Panagopoulos et al, 2006), SQSTM1 (Iyevleva et al, 2015; Takeuchi et al, 2011), TPR (Choi et al, 2014), WDCP (Lipson et al, 2012), RRBP1 (Lee et al, 2017), DCTN1 (Subbiah et al, 2015; Lee et al, 2017; Iyevleva et al, 2015; Wang et al, 2012; Wiesner et al, 2014), EEF1A (van der Krogt et al, 2017), BIRC6 (Shan et al, 2015), EIF2AK3 (Ali et al, 2016), PPM1B (Ali et al, 2016), PRKAR1A (Ali et al, 2016), GCC2 (Noh et al, 2017), BCL11A (Tian et al, 2007) and LMO7 (Noh et al, 2017).

Literature References
PubMed ID Title Journal Year
22347464 KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only

Sugawara, E, Sakata, S, Soda, M, Togashi, Y, Hatano, S, Takeuchi, K, Mano, H, Asaka, R, Nakajima, T

PLoS One 2012
28659337 Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC- and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene

Ferreiro, JF, Tousseyn, T, Uyttebroeck, A, Michaux, L, Devos, T, Cools, J, Geerdens, E, Jacobs, K, Wlodarska, I, Doms, K, Bempt, MV, van der Krogt, JA, Pierre, P, Vandenberghe, P, Pluys, U, Mentens, N

Haematologica 2017
24613930 Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer

Altschuler, DL, Nikiforov, YE, Ferris, RL, Hodak, SP, Liu, P, Kelly, LM, Nikiforova, MN, Yu, YP, Dacic, S, Trivedi, S, Luo, J, Barila, G, Panebianco, F, Gandhi, M, Carty, SE, Evdokimova, VN

Proc Natl Acad Sci U S A 2014
27573755 The role of the ALK receptor in cancer biology

Hallberg, B, Palmer, RH

Ann Oncol 2016
28741662 Molecular breakdown: a comprehensive view of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer

Choi, YL, Lee, SH, Shin, HT, Kim, M, Oh, DY, Lee, MS, Sung, M, Noh, KW, Kim, YJ, Park, WY, Shim, YM, Lee, SE, An, S, Zo, JI, Song, JY, Han, J, Jung, K, Kim, J

J Pathol 2017
12920229 ALK+, CD30-, CD20- large B-cell lymphoma containing anaplastic lymphoma kinase (ALK) fused to clathrin heavy chain gene (CLTC)

Nagasawa, T, Kojima, H, Yamashita, Y, Mori, N, Shinagawa, A, Suzukawa, K, Ozawa, H, Chikatsu, N

Mod Pathol 2003
10702393 ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35)

Liu, J, Garicochea, B, Colleoni, GW, Filippa, DA, Ladanyi, M, Bridge, JA

Am J Pathol 2000
21164297 Epithelioid inflammatory myofibroblastic sarcoma: An aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK

Wang, WL, Hornick, JL, Roy, A, Coffin, CM, Mariño-Enríquez, A, Lazar, AJ, Lopez-Terrada, D, Fletcher, CD

Am. J. Surg. Pathol. 2011
26062823 STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion

Ali, SM, Patel, S, McMahon, C, Ross, JS, Ganeshan, DM, Brennan, T, Levenback, CF, Elvin, JA, Subbiah, V, Mayfield, J, Silva, EG, Ohaji, C, Stephens, PJ, Zinner, R, Miller, VA, Chmielecki, J, Berry, J, Chalmers, ZR, Subbiah, IM, Anand, D

J Hematol Oncol 2015
11943732 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

Bellosillo, B, Morris, SW, Pulford, K, Rosenwald, A, Beà, S, Mason, D, Hernández, L, Pinyol, M, Ott, G, Falini, B, Santos, E, Fernández, A, Carbone, A, Campo, E

Am. J. Pathol. 2002
24445538 Kinase fusions are frequent in Spitz tumours and spitzoid melanomas

Palmedo, G, Botton, T, Yeh, I, Busam, KJ, Garrido, M, Cerroni, L, Bastian, BC, Murali, R, Wiesner, T, Kutzner, H, Ross, JS, Lipson, D, Cronin, MT, Berger, MF, He, J, Esteve-Puig, R, Stephens, PJ, Brennan, K, Miller, VA, Sparatta, A, Otto, G, Yelensky, R

Nat Commun 2014
10934142 TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors

Pinkus, GS, Pinkus, JL, Rubin, BP, Perez-Atayde, A, Hibbard, MK, Fletcher, JA, Xiao, S, Yi, ES, Fletcher, CD, Lawrence, B, Dal Cin, P

Am J Pathol 2000
25813404 Novel ALK fusion partners in lung cancer

Pozharisski, KM, Aleksakhina, SN, Imyanitov, EN, Togo, AV, Sokolenko, AP, Ivantsov, AO, Mitiushkina, NV, Merkulov, VO, Strelkova, TN, Iyevleva, AG, Garifullina, AR, Tiurin, VI, Kuligina, ESh, Raskin, GA

Cancer Lett 2015
12750159 ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma

Marynen, P, Simons, A, De Paepe, P, Stul, M, Baens, M, Speleman, F, Brons, P, Praet, M, Laureys, G, Poppe, B, Wlodarska, I, De Wolf-Peeters, C, Verhasselt, B, van Krieken, H, Vandenberghe, P

Blood 2003
21134980 Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma

Ota, Y, Soda, M, Togashi, Y, Hatano, S, Noguchi, M, Takeuchi, K, Mano, H, Asaka, R, Sekiguchi, Y

Haematologica 2011
27874193 ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma

Fletcher, JA, Hornick, JL, Lee, CT, Ou, WB, Mariño-Enríquez, A, Li, CF, Lee, JC, Zhu, MJ, Huang, HY

J. Pathol. 2017
27245569 Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization

Ganesan, S, Hensing, T, Nowak, J, Ou, SH, Allen, J, Ross, JS, Wakelee, H, Schrock, AB, He, J, Zakowski, M, Frampton, GM, Gowen, K, Miller, VA, Menon, S, Chmielecki, J, Ladanyi, M, Molina, JR, Zauderer, M, Klempner, SJ, Peled, N, Firozvi, K, Ali, SM, Stephens, PJ, Fischbach, N, MacMahon, H, Lipson, D, Suh, JH, Sanford, E, Salgia, R, Elvin, JA, Chalmers, Z, Brahmer, JR, Yelensky, R, Kulkarni, A

Oncologist 2016
21415216 Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer

Jänne, PA, Takezawa, K, Nishio, K, Nakagawa, K, Okamoto, I

Clin. Cancer Res. 2011
8633037 Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5)

Yamamoto, T, Iwahara, T, Satoh, H, Seki, N, Fujimoto, J, Mori, S, Shiota, M

Proc. Natl. Acad. Sci. U.S.A. 1996
17625570 Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer

Ishikawa, Y, Watanabe, H, Hatanaka, H, Soda, M, Sugiyama, Y, Takada, S, Choi, YL, Yamashita, Y, Aburatani, H, Niki, T, Enomoto, M, Mano, H, Fujiwara, S, Ishikawa, S, Ohno, S, Bando, M, Kurashina, K, Sohara, Y

Nature 2007
22327622 Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies

Zwirko, Z, Donahue, A, Soussan-Gutman, L, Nechushtan, H, Balasubramanian, S, Brennan, KW, Ross, JS, Juhn, F, Bloom, T, Frampton, GM, Capelletti, M, White, J, Jarosz, M, Kim, J, Park, SI, Kim, HR, Otto, G, Sasaki, H, Ercan, D, White, E, Downing, SR, Jänne, PA, Parker, A, Mitchell, KC, Lipson, D, Garcia, L, Cronin, MT, Sheehan, CE, Stephens, PJ, Yelensky, R, Curran, JA, Peretz, T

Nat. Med. 2012
28404650 Identification of a novel crizotinib-sensitive BCL11A-ALK gene fusion in a nonsmall cell lung cancer patient

Li, ZW, Deng, WJ, Tian, Q

Eur Respir J 2017
24475247 Identification of a recurrent STRN/ALK fusion in thyroid carcinomas

Soubeyran, I, Savagner, F, Bonichon, F, Hostein, I, Ribeiro, A, Godbert, Y, Bonhomme, B, Boutet-Bouzamondo, N, Pérot, G, Chibon, F

PLoS One 2014
10556217 TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations

Falini, B, Delsol, G, Hernández, S, Rosenwald, A, Beà, S, Campo, E, Lamant, L, Hernández, L, Mason, DY, Pinyol, M, Ott, G, Pulford, K

Blood 1999
18701132 An inflammatory myofibroblastic tumor in liver with ALK and RANBP2 gene rearrangement: combination of distinct morphologic, immunohistochemical, and genetic features

Chen, ST, Lee, JC

Hum. Pathol. 2008
23661334 Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing

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J. Pathol. 2013
24736082 A novel fusion of TPR and ALK in lung adenocarcinoma

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J Thorac Oncol 2014
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Roskoski, R

Pharmacol. Res. 2013
21213368 ALK rearrangement in sickle cell trait-associated renal medullary carcinoma

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Genes Chromosomes Cancer 2011
15208656 Differential effects of X-ALK fusion proteins on proliferation, transformation, and invasion properties of NIH3T3 cells

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Oncogene 2004
24518094 HIP1-ALK, a novel fusion protein identified in lung adenocarcinoma

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J Thorac Oncol 2014
23957430 Inflammatory myofibroblastic tumour of the lung with a novel PPFIBP1-ALK fusion variant

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Histopathology 2013
26001147 BIRC6-ALK, a Novel Fusion Gene in ALK Break-Apart FISH-Negative Lung Adenocarcinoma, Responds to Crizotinib

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J Thorac Oncol 2015
21656749 A novel KIF5B-ALK variant in nonsmall cell lung cancer

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Cancer 2011
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Blood 1999
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Cancer Res 2000
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Mol. Cancer 2018
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Blood 2000
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J Thorac Oncol 2014
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Marynen, P, De Wolf-Peeters, C, Pauwels, P, Somers, R, Hagemeijer, A, Pedeutour, F, Mentens, N, Cools, J, Maes, B, Wlodarska, I

Genes Chromosomes Cancer 2002
24060861 Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

Palmer, RH, Hallberg, B

Nat. Rev. Cancer 2013
22658521 Fusion of dynactin 1 to anaplastic lymphoma kinase in inflammatory myofibroblastic tumor

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Hum Pathol 2012
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J Thorac Oncol 2014
7824924 Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma

Morris, SW, Shapiro, DN, Kirstein, MN, Saltman, DL, Look, AT, Valentine, MB, Dittmer, K

Science 1995
16161041 Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor

Mandahl, N, Panagopoulos, I, Isaksson, M, Domanski, HA, Lindblom, P, Mertens, F, Nilsson, T

Int J Cancer 2006
21494621 Inhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC-ALK-positive human diffuse large B cell lymphomas

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PLoS One 2011
11310834 Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma

Touriol, C, Delsol, G, Kluin-Nelemans, HC, Roncador, G, Mason, D, Campo, E, Hernández, L, Tort, F, Kluin, P, Nayach, I, Pinyol, M, Pulford, K

Lab Invest 2001
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cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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