Anaplastic lymphoma kinase (ALK) was first identified in 1994 with the discovery that the gene encoding for this kinase was involved in the t(2;5)(p23;q35) chromosomal translocation observed in a subset of anaplastic large cell lymphoma (ALCL). The NPM-ALK fusion protein generated by this translocation is a constitutively active tyrosine kinase, and much research has focused on characterizing the signalling pathways and cellular activities this oncoprotein regulates in ALCL. We now know about the existence of nearly 20 distinct ALK translocation partners, and the fusion proteins resulting from these translocations play a critical role in the pathogenesis of a variety of cancers including subsets of large B-cell lymphomas, nonsmall cell lung carcinomas, and inflammatory myofibroblastic tumours. Moreover, the inhibition of ALK has been shown to be an effective treatment strategy in some of these malignancies. In this paper we will highlight malignancies where ALK translocations have been identified and discuss why ALK fusion proteins are constitutively active tyrosine kinases. Finally, using ALCL as an example, we will examine three key signalling pathways activated by NPM-ALK that contribute to proliferation and survival in ALCL. 1. The ALK Receptor Tyrosine Kinase Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase of the insulin receptor superfamily, and in mice and humans, the normal expression of ALK is largely restricted to the brain and nervous system [1–4]. Mice deficient in ALK appear to have no overt developmental abnormalities [5–8]; however, behavioural abnormalities have been noted in these mice. ALK-deficient mice perform better on tests of cognitive ability and display less anxiety than their wild-type littermate controls [6, 7]. Behavioural tests also demonstrated increased alcohol consumption and altered sensitivity to alcohol in ALK-deficient mice compared to wild-type littermates [8]. Intriguingly, single-nucleotide polymorphisms (SNPs) in ALK have been identified in humans that correlate with decreased response to alcohol [8]. A correlation between ALK SNPs and schizophrenia has also been noted in a Japanese study [9]. In Drosophila melanogaster, the jelly belly protein (Jeb) has been characterized as an ALK ligand [10–12]. In mammals, there does not appear to be a Jeb homologue but two ligands for ALK have been described, pleiotrophin [13] and midkine [14]. However, there is not complete agreement regarding whether these are indeed ALK stimulating ligands [15, 16]. More recently, Perez-Pinera and colleagues proposed an
References
[1]
K. Pulford, L. Lamant, S. W. Morris et al., “Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1,” Blood, vol. 89, no. 4, pp. 1394–1404, 1997.
[2]
T. Iwahara, J. Fujimoto, D. Wen et al., “Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system,” Oncogene, vol. 14, no. 4, pp. 439–449, 1997.
[3]
S. W. Morris, C. Naeve, P. Mathew et al., “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, vol. 14, no. 18, pp. 2175–2188, 1997.
[4]
E. Vernersson, N. K. S. Khoo, M. L. Henriksson, G. Roos, R. H. Palmer, and B. Hallberg, “Characterization of the expression of the ALK receptor tyrosine kinase in mice,” Gene Expression Patterns, vol. 6, no. 5, pp. 448–461, 2006.
[5]
R. H. Palmer, E. Vernersson, C. Grabbe, and B. Hallberg, “Anaplastic lymphoma kinase: signalling in development and disease,” Biochemical Journal, vol. 420, no. 3, pp. 345–361, 2009.
[6]
J. B. Weiss, C. Xue, T. Benice, L. Xue, S. W. Morris, and J. Raber, “Anaplastic lymphoma kinase and leukocyte tyrosine kinase: functions and genetic interactions in learning, memory and adult neurogenesis,” Pharmacology, Biochemistry, and Behavior, vol. 100, no. 3, pp. 566–574, 2012.
[7]
J. G. Bilsland, A. Wheeldon, A. Mead et al., “Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications,” Neuropsychopharmacology, vol. 33, no. 3, pp. 685–700, 2008.
[8]
A. W. Lasek, J. Lim, C. L. Kliethermes et al., “An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol,” PLoS ONE, vol. 6, no. 7, Article ID e22636, 2011.
[9]
H. Kunugi, R. Hashimoto, T. Okada et al., “Possible association between nonsynonymous polymorphisms of the anaplastic lymphoma kinase (ALK) gene and schizophrenia in a Japanese population,” Journal of Neural Transmission, vol. 113, no. 10, pp. 1569–1573, 2006.
[10]
C. Englund, C. E. Lorén, C. Grabbe et al., “Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion,” Nature, vol. 425, no. 6957, pp. 512–516, 2003.
[11]
H. H. Lee, A. Norris, J. B. Weiss, and M. Frasch, “Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers,” Nature, vol. 425, no. 6957, pp. 507–512, 2003.
[12]
C. Stute, K. Schimmelpfeng, R. Renkawitz-Pohl, R. H. Palmer, and A. Holz, “Myoblast determination in the somatic and visceral mesoderm depends on Notch signalling as well as on milliways (miliAlk) as receptor for jeb signalling,” Development, vol. 131, no. 4, pp. 743–754, 2004.
[13]
G. E. Stoica, A. Kuo, A. Aigner et al., “Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin,” Journal of Biological Chemistry, vol. 276, no. 20, pp. 16772–16779, 2001.
[14]
G. E. Stoica, A. Kuo, C. Powers et al., “Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types,” Journal of Biological Chemistry, vol. 277, no. 39, pp. 35990–35998, 2002.
[15]
C. Moog-Lutz, J. Degoutin, J. Y. Gouzi et al., “Activation and inhibition of anaplastic lymphoma kinase receptor tyrosine kinase by monoclonal antibodies and absence of agonist activity of pleiotrophin,” Journal of Biological Chemistry, vol. 280, no. 28, pp. 26039–26048, 2005.
[16]
A. Motegi, J. Fujimoto, M. Kotani, H. Sakuraba, and T. Yamamoto, “ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth,” Journal of Cell Science, vol. 117, no. 15, pp. 3319–3329, 2004.
[17]
P. Perez-Pinera, W. Zhang, Y. Chang, J. A. Vega, and T. F. Deuel, “Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor protein-tyrosine phosphatase β/ζ signaling pathway: an alternative mechanism of receptor tyrosine kinase activation,” Journal of Biological Chemistry, vol. 282, no. 39, pp. 28683–28690, 2007.
[18]
J. Mourali, A. Bénard, F. C. Louren？o et al., “Anaplastic lymphoma kinase is a dependence receptor whose proapoptotic functions are activated by caspase cleavage,” Molecular and Cellular Biology, vol. 26, no. 16, pp. 6209–6222, 2006.
[19]
P. Mehlen and D. E. Bredesen, “The dependence receptor hypothesis,” Apoptosis, vol. 9, no. 1, pp. 37–49, 2004.
[20]
S. W. Morris, M. N. Kirstein, M. B. Valentine et al., “Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma,” Science, vol. 263, no. 5151, pp. 1281–1284, 1994.
[21]
M. Shiota, J. Fujimoto, T. Semba, H. Satoh, T. Yamamoto, and S. Mori, “Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3,” Oncogene, vol. 9, no. 6, pp. 1567–1574, 1994.
[22]
D. A. Arber, L. H. Sun, and L. M. Weiss, “Detection of the t(2;5)(p23;q35) chromosomal translocation in large B- cell lymphomas other than anaplastic large cell lymphoma,” Human Pathology, vol. 27, no. 6, pp. 590–594, 1996.
[23]
L. Lamant, N. Dastugue, K. Pulford, G. Delsol, and B. Mariamé, “A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation,” Blood, vol. 93, no. 9, pp. 3088–3095, 1999.
[24]
R. Siebert, S. Gesk, L. Harder et al., “Complex variant translocation t(1;2) with TPM3-ALK fusion due to cryptic ALK gene rearrangement in anaplastic large-cell lymphoma,” Blood, vol. 94, no. 10, pp. 3614–3617, 1999.
[25]
B. Lawrence, A. Perez-Atayde, M. K. Hibbard et al., “TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors,” American Journal of Pathology, vol. 157, no. 2, pp. 377–384, 2000.
[26]
E. Sugawara, Y. Togashi, N. Kuroda, et al., “Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method,” Cancer. In press.
[27]
L. Hernández, M. Pinyol, S. Hernández et al., “TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations,” Blood, vol. 94, no. 9, pp. 3265–3268, 1999.
[28]
K. Rikova, A. Guo, Q. Zeng et al., “Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer,” Cell, vol. 131, no. 6, pp. 1190–1203, 2007.
[29]
M. Trinei, L. Lanfrancone, E. Campo et al., “A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma,” Cancer Research, vol. 60, no. 4, pp. 793–798, 2000.
[30]
Z. Ma, J. Cools, P. Marynen et al., “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,” Blood, vol. 95, no. 6, pp. 2144–2149, 2000.
[31]
G. W. B. Colleoni, J. A. Bridge, B. Garicochea, J. Liu, D. A. Filippa, and M. Ladanyi, “ATIC-ALK: a novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35),” American Journal of Pathology, vol. 156, no. 3, pp. 781–789, 2000.
[32]
M. Debiec-Rychter, P. Marynen, A. Hagemeijer, and P. Pauwels, “ALK-ATIC fusion in urinary bladder inflammatory myofibroblastic tumor,” Genes Chromosomes and Cancer, vol. 38, no. 2, pp. 187–190, 2003.
[33]
C. Touriol, C. Greenland, L. Lamant et al., “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),” Blood, vol. 95, no. 10, pp. 3204–3207, 2000.
[34]
J. A. Bridge, M. Kanamori, Z. Ma et al., “Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor,” American Journal of Pathology, vol. 159, no. 2, pp. 411–415, 2001.
[35]
P. De Paepe, M. Baens, H. van Krieken et al., “ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma,” Blood, vol. 102, no. 7, pp. 2638–2641, 2003.
[36]
R. D. Gascoyne, L. Lamant, J. I. Martin-Subero et al., “ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases,” Blood, vol. 102, no. 7, pp. 2568–2573, 2003.
[37]
N. Chikatsu, H. Kojima, K. Suzukawa et al., “ALK+, CD30-, CD20- large B-cell lymphoma containing anaplastic lymphoma kinase (ALK) fused to clathrin heavy chain gene (CLTC),” Modern Pathology, vol. 16, no. 8, pp. 828–832, 2003.
[38]
W. Y. Wang, L. Gu, W. P. Liu, G. D. Li, H. J. Liu, and Z. G. Ma, “ALK-positive extramedullary plasmacytoma with expression of the CLTC-ALK fusion transcript,” Pathology, Research and Practice, vol. 207, no. 9, pp. 587–591, 2011.
[39]
S. J. Meech, L. McGavran, L. F. Odom et al., “Unusual childhood extramedullary hematologic malignancy with natural killer cell properties that contains tropomyosin 4—anaplastic lymphoma kinase gene fusion,” Blood, vol. 98, no. 4, pp. 1209–1216, 2001.
[40]
F. R. Jazii, Z. Najafi, R. Malekzadeh et al., “Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer,” World Journal of Gastroenterology, vol. 12, no. 44, pp. 7104–7112, 2006.
[41]
X. L. Du, H. Hu, D. C. Lin et al., “Proteomic profiling of proteins dysregulted in Chinese esophageal squamous cell carcinoma,” Journal of Molecular Medicine, vol. 85, no. 8, pp. 863–875, 2007.
[42]
F. Tort, M. Pinyol, K. Pulford et al., “Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma,” Laboratory Investigation, vol. 81, no. 3, pp. 419–426, 2001.
[43]
J. Cools, I. Wlodarska, R. Somers et al., “Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor,” Genes Chromosomes and Cancer, vol. 34, no. 4, pp. 354–362, 2002.
[44]
Z. Ma, D. A. Hill, M. H. Collins et al., “Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor,” Genes Chromosomes and Cancer, vol. 37, no. 1, pp. 98–105, 2003.
[45]
L. Lamant, R. D. Gascoyne, M. M. Duplantier et al., “Non-muscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma,” Genes Chromosomes and Cancer, vol. 37, no. 4, pp. 427–432, 2003.
[46]
I. Panagopoulos, T. Nilsson, H. A. Domanski et al., “Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor,” International Journal of Cancer, vol. 118, no. 5, pp. 1181–1186, 2006.
[47]
K. Van Roosbroeck, J. Cools, D. Dierickx et al., “ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions,” Haematologica, vol. 95, no. 3, pp. 509–513, 2010.
[48]
C. Bedwell, D. Rowe, D. Moulton, G. Jones, N. Bown, and C. M. Bacon, “Cytogenetically complex SEC31A-ALK fusions are recurrent in ALK-positive large B-cell lymphomas,” Haematologica, vol. 96, no. 2, pp. 343–346, 2011.
[49]
M. Soda, Y. L. Choi, M. Enomoto et al., “Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer,” Nature, vol. 448, no. 7153, pp. 561–566, 2007.
[50]
E. Lin, L. Li, Y. Guan et al., “Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers,” Molecular Cancer Research, vol. 7, no. 9, pp. 1466–1476, 2009.
[51]
K. Takeuchi, M. Soda, Y. Togashi et al., “Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma,” Haematologica, vol. 96, no. 3, pp. 464–467, 2011.
[52]
L. V. Debelenko, S. C. Raimondi, N. Daw et al., “Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum,” Modern Pathology, vol. 24, no. 3, pp. 430–442, 2011.
[53]
A. Mari？o-Enríquez, W. B. Ou, C. B. Weldon, J. A. Fletcher, and A. R. Pérez-Atayde, “ALK rearrangement in sickle cell trait-associated renal medullary carcinoma,” Genes Chromosomes and Cancer, vol. 50, no. 3, pp. 146–153, 2011.
[54]
K. Takeuchi, L. C. Young, Y. Togashi et al., “KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer,” Clinical Cancer Research, vol. 15, no. 9, pp. 3143–3149, 2009.
[55]
K. Takeuchi, M. Soda, Y. Togashi et al., “Pulmonary inflammatory myofibroblastic tumor expressing a novel fusion, PPFIBP1-ALK: reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion identification,” Clinical Cancer Research, vol. 17, no. 10, pp. 3341–3348, 2011.
[56]
D. Lipson, M. Capelletti, R. Yelensky, et al., “Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies,” Nature Medicine, vol. 18, no. 3, pp. 382–384, 2012.
[57]
Y. Togashi, M. Soda, S. Sakata, et al., “KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only,” PLoS ONE, vol. 7, no. 2, Article ID e31323, 2012.
[58]
G. Delsol, B. Falini, H. K. Muller-Hermelink, et al., Anaplastic Large Cell Lymphoma (ALCL), ALK-Positive, International Agency for Research on Cancer (IARC), Lyon, France, 4th edition, 2008.
[59]
A. Fornari, R. Piva, R. Chiarle, D. Novero, and G. Inghirami, “Anaplastic large cell lymphoma: one or more entities among T-cell lymphoma?” Hematological Oncology, vol. 27, no. 4, pp. 161–170, 2009.
[60]
P. Fischer, E. Nacheva, D. Y. Mason et al., “A Ki-1 (CD30)-positive human cell line (Karpas 299) established from a high grade non-Hodgkin's lymphoma, showing a 2;5 translocation and rearrangement of the T-cell receptor β-chain gene,” Blood, vol. 72, no. 1, pp. 234–240, 1988.
[61]
R. Rimokh, J. P. Magaud, F. Berger et al., “A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma (Ki-1 lymphoma),” British Journal of Haematology, vol. 71, no. 1, pp. 31–36, 1989.
[62]
Y. Kaneko, G. Frizzera, S. Edamura et al., “A novel translocation, t(2;5)(p23;q35), in childhood phagocytic large T-cell lymphoma mimicking malignant histiocytosis,” Blood, vol. 73, no. 3, pp. 806–813, 1989.
[63]
D. Y. Mason, C. Bastard, R. Rimokh et al., “CD30-positive large cell lymphomas (Ki-1 lymphoma) are associated with a chromosomal translocation involving 5q35,” British Journal of Haematology, vol. 74, no. 2, pp. 161–168, 1990.
[64]
M. M. Le Beau, M. A. Bitter, R. A. Larson et al., “The t(2;5)(p23;q35): a recurring chromosomal abnormality in Ki-1-positive anaplastic large cell lymphoma,” Leukemia, vol. 3, no. 12, pp. 866–870, 1989.
[65]
C. A. Griffin, A. L. Hawkins, C. Dvorak, C. Henkle, T. Ellingham, and E. J. Perlman, “Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors,” Cancer Research, vol. 59, no. 12, pp. 2776–2780, 1999.
[66]
C. Gambacorti-Passerini, C. Messa, and E. M. Pogliani, “Crizotinib in anaplastic large-cell lymphoma,” The New England Journal of Medicine, vol. 364, no. 8, pp. 775–776, 2011.
[67]
E. L. Kwak, Y. J. Bang, D. R. Camidge et al., “Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer,” The New England Journal of Medicine, vol. 363, no. 18, pp. 1693–1703, 2010.
[68]
J. E. Butrynski, D. R. D'Adamo, J. L. Hornick et al., “Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor,” The New England Journal of Medicine, vol. 363, no. 18, pp. 1727–1733, 2010.
[69]
P. Perez-Pinera, Y. Chang, A. Astudillo, J. Mortimer, and T. F. Deuel, “Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer,” Biochemical and Biophysical Research Communications, vol. 358, no. 2, pp. 399–403, 2007.
[70]
L. Lamant, K. Pulford, D. Bischof et al., “Expression of the ALK tyrosine kinase gene in neuroblastoma,” American Journal of Pathology, vol. 156, no. 5, pp. 1711–1721, 2000.
[71]
I. Janoueix-Lerosey, D. Lequin, L. Brugières et al., “Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma,” Nature, vol. 455, no. 7215, pp. 967–970, 2008.
[72]
Y. Chen, J. Takita, Y. L. Choi et al., “Oncogenic mutations of ALK kinase in neuroblastoma,” Nature, vol. 455, no. 7215, pp. 971–974, 2008.
[73]
R. E. George, T. Sanda, M. Hanna et al., “Activating mutations in ALK provide a therapeutic target in neuroblastoma,” Nature, vol. 455, no. 7215, pp. 975–978, 2008.
[74]
H. Carén, F. Abel, P. Kogner, and T. Martinsson, “High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours,” Biochemical Journal, vol. 416, no. 2, pp. 153–159, 2008.
[75]
Y. P. Mossé, M. Laudenslager, L. Longo et al., “Identification of ALK as a major familial neuroblastoma predisposition gene,” Nature, vol. 455, no. 7215, pp. 930–935, 2008.
[76]
A. K. Murugan and M. M. Xing, “Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene,” Cancer Research, vol. 71, no. 13, pp. 4403–4411, 2011.
[77]
D. Wang, H. Umekawa, and M. O. J. Olson, “Expression and subcellular locations of two forms of nucleolar protein B23 in rat tissues and cells,” Cellular and Molecular Biology Research, vol. 39, no. 1, pp. 33–42, 1993.
[78]
R. A. Borer, C. F. Lehner, H. M. Eppenberger, and E. A. Nigg, “Major nucleolar proteins shuttle between nucleus and cytoplasm,” Cell, vol. 56, no. 3, pp. 379–390, 1989.
[79]
E. Colombo, M. Alcalay, and P. G. Pelicci, “Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases,” Oncogene, vol. 30, no. 23, pp. 2595–2609, 2011.
[80]
J. Fujimoto, M. Shiota, T. Iwahara et al., “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, vol. 93, no. 9, pp. 4181–4186, 1996.
[81]
D. Bischof, K. Pulford, D. Y. Mason, and S. W. Morris, “Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma- associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis,” Molecular and Cellular Biology, vol. 17, no. 4, pp. 2312–2325, 1997.
[82]
P. K. Chan, “Cross-linkage of nucleophosmin in tumor cells by nitrogen mustard,” Cancer Research, vol. 49, no. 12, pp. 3271–3275, 1989.
[83]
B. Y. M. Yung and P. K. Chan, “Identification and characterization of a hexameric form of nucleolar phosphoprotein B23,” Biochimica et Biophysica Acta, vol. 925, no. 1, pp. 74–82, 1987.
[84]
H. Mano, “Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer,” Cancer Science, vol. 99, no. 12, pp. 2349–2355, 2008.
[85]
A. Barreca, E. Lasorsa, L. Riera et al., “Anaplastic lymphoma kinase in human cancer,” Journal of Molecular Endocrinology, vol. 47, no. 1, pp. R11–R23, 2011.
[86]
R. Chiarle, C. Voena, C. Ambrogio, R. Piva, and G. Inghirami, “The anaplastic lymphoma kinase in the pathogenesis of cancer,” Nature Reviews Cancer, vol. 8, no. 1, pp. 11–23, 2008.
[87]
D. E. Levy and J. E. Darnell, “STATs: transcriptional control and biological impact,” Nature Reviews Molecular Cell Biology, vol. 3, no. 9, pp. 651–662, 2002.
[88]
C. I. Santos and A. P. Costa-Pereira, “Signal transducers and activators of transcription-from cytokine signalling to cancer biology,” Biochimica et Biophysica Acta, vol. 1816, no. 1, pp. 38–49, 2011.
[89]
Q. Zhang, P. N. Raghunath, L. Xue et al., “Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma,” Journal of Immunology, vol. 168, no. 1, pp. 466–474, 2002.
[90]
A. Zamo, R. Chiarle, R. Piva et al., “Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death,” Oncogene, vol. 21, no. 7, pp. 1038–1047, 2002.
[91]
J. D. Khoury, L. J. Medeiros, G. Z. Rassidakis et al., “Differential expression and clinical significance of tyrosine-phosphorylated STAT3 in ALK+ and ALK- anaplastic large cell lymphoma,” Clinical Cancer Research, vol. 9, no. 10, part 1, pp. 3692–3699, 2003.
[92]
R. Chiarle, J. Z. Gong, I. Guasparri et al., “NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors,” Blood, vol. 101, no. 5, pp. 1919–1927, 2003.
[93]
R. Chiarle, W. J. Simmons, H. Cai et al., “Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target,” Nature Medicine, vol. 11, no. 6, pp. 623–629, 2005.
[94]
H. M. Amin, T. J. McDonnell, Y. Ma et al., “Selective inhibition of STAT3 induces apoptosis and G1 cell cycle arrest in ALK-positive anaplastic large cell lymphoma,” Oncogene, vol. 23, no. 32, pp. 5426–5434, 2004.
[95]
R. Piva, L. Agnelli, E. Pellegrino et al., “Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms,” Journal of Clinical Oncology, vol. 28, no. 9, pp. 1583–1590, 2010.
[96]
Q. Zhang, H. Wang, K. Kantekure, et al., “Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS,” Blood, vol. 118, no. 11, pp. 3062–3071, 2011.
[97]
N. Anastasov, I. Bonzheim, M. Rudelius et al., “C/EBPβ expression in ALK-positiveanaplastic large cell lymphomas is required for cell proliferation and is induced by the STAT3 signaling pathway,” Haematologica, vol. 95, no. 5, pp. 760–767, 2010.
[98]
R. Piva, E. Pellegrino, M. Mattioli et al., “Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and BCl2A1 as critical target genes,” Journal of Clinical Investigation, vol. 116, no. 12, pp. 3171–3182, 2006.
[99]
M. Marzec, Q. Zhang, A. Goradia et al., “Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1),” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 52, pp. 20852–20857, 2008.
[100]
R. Yamamoto, M. Nishikori, M. Tashima et al., “B7-H1 expression is regulated by MEK/ERK signaling pathway in anaplastic large cell lymphoma and Hodgkin lymphoma,” Cancer Science, vol. 100, no. 11, pp. 2093–2100, 2009.
[101]
R. Lai, G. Z. Rassidakis, L. J. Medeiros et al., “Signal transducer and activator of transcription-3 activation contributes to high tissue inhibitor of metalloproteinase-1 expression in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma,” American Journal of Pathology, vol. 164, no. 6, pp. 2251–2258, 2004.
[102]
M. Marzec, X. Liu, W. Wong et al., “Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA,” Oncogene, vol. 30, no. 11, pp. 1372–1378, 2011.
[103]
J. Zhang, P. Wang, F. Wu, et al., “Aberrant expression of the transcriptional factor Twist1 promotes invasiveness in ALK-positive anaplastic large cell lymphoma,” Cellular Signalling, vol. 24, no. 4, pp. 852–858, 2012.
[104]
M. Kasprzycka, M. Marzec, X. Liu, Q. Zhang, and M. A. Wasik, “Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 26, pp. 9964–9969, 2006.
[105]
C. Ambrogio, C. Martinengo, C. Voena et al., “NPM-ALK oncogenic tyrosine kinase controls T-cell identity by transcriptional regulation and epigenetic silencing in lymphoma cells,” Cancer Research, vol. 69, no. 22, pp. 8611–8619, 2009.
[106]
N. Sasai and P. A. Defossez, “Many paths to one goal? The proteins that recognize methylated DNA in eukaryotes,” The International Journal of Developmental Biology, vol. 53, no. 2-3, pp. 323–334, 2009.
[107]
Q. Zhang, H. Y. Wang, X. Liu, G. Bhutani, K. Kantekure, and M. Wasik, “IL-2R common γ-chain is epigenetically silenced by nucleophosphin-anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 29, pp. 11977–11982, 2011.
[108]
Q. Zhang, H. Y. Wang, X. Liu, and M. A. Wasik, “STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression,” Nature Medicine, vol. 13, no. 11, pp. 1341–1348, 2007.
[109]
D. K. Crockett, Z. Lin, K. S. J. Elenitoba-Johnson, and M. S. Lim, “Identification of NPM-ALK interacting proteins by tandem mass spectrometry,” Oncogene, vol. 23, no. 15, pp. 2617–2629, 2004.
[110]
H. M. Amin, L. J. Medeiros, Y. Ma et al., “Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma,” Oncogene, vol. 22, no. 35, pp. 5399–5407, 2003.
[111]
M. Marzec, M. Kasprzycka, A. Ptasznik et al., “Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3,” Laboratory Investigation, vol. 85, no. 12, pp. 1544–1554, 2005.
[112]
J. D. Khoury, G. Z. Rassidakis, L. J. Medeiros, H. M. Amin, and R. Lai, “Methylation of SHP1 gene and loss of SHP1 protein expression are frequent in systemic anaplastic large cell lymphoma,” Blood, vol. 104, no. 5, pp. 1580–1581, 2004.
[113]
Q. Zhang, H. Y. Wang, M. Marzec, P. N. Raghunath, T. Nagasawa, and M. A. Wasik, “STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 19, pp. 6948–6953, 2005.
[114]
J. F. Honorat, A. Ragab, L. Lamant, G. Delsol, and J. Ragab-Thomas, “SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling,” Blood, vol. 107, no. 10, pp. 4130–4138, 2006.
[115]
Y. Han, H. M. Amin, B. Franko, C. Frantz, X. Shi, and R. Lai, “Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma,” Blood, vol. 108, no. 8, pp. 2796–2803, 2006.
[116]
Y. Han, H. M. Amin, C. Frantz et al., “Restoration of shp1 expression by 5-AZA-2′-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma,” Leukemia, vol. 20, no. 9, pp. 1602–1609, 2006.
[117]
L. Qiu, R. Lai, Q. Lin et al., “Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells,” Blood, vol. 108, no. 7, pp. 2407–2415, 2006.
[118]
J. D. Bard, P. Gelebart, M. Anand et al., “IL-21 contributes to JAK3/STAT3 activation and promotes cell growth in ALK-positive anaplastic large cell lymphoma,” American Journal of Pathology, vol. 175, no. 2, pp. 825–834, 2009.
[119]
J. D. Bard, P. Gelebart, M. Anand, H. M. Amin, and R. Lai, “Aberrant expression of IL-22 receptor 1 and autocrine IL-22 stimulation contribute to tumorigenicity in ALK+ anaplastic large cell lymphoma,” Leukemia, vol. 22, no. 8, pp. 1595–1603, 2008.
[120]
C. R. Geest and P. J. Coffer, “MAPK signaling pathways in the regulation of hematopoiesis,” Journal of Leukocyte Biology, vol. 86, no. 2, pp. 237–250, 2009.
[121]
L. S. Steelman, R. A. Franklin, S. L. Abrams et al., “Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy,” Leukemia, vol. 25, no. 7, pp. 1080–1094, 2011.
[122]
M. Watanabe, M. Sasaki, K. Itoh et al., “JunB induced by constitutive CD30-extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling activates the CD30 promoter in anaplastic large cell lymphoma and Reed-Sternberg cells of Hodgkin lymphoma,” Cancer Research, vol. 65, no. 17, pp. 7628–7634, 2005.
[123]
P. B. Staber, P. Vesely, N. Haq et al., “The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling,” Blood, vol. 110, no. 9, pp. 3374–3383, 2007.
[124]
M. Marzec, M. Kasprzycka, X. Liu, P. N. Raghunath, P. Wlodarski, and M. A. Wasik, “Oncogenic tyrosine kinase NPM/ALK induces activation of the MEK/ERK signaling pathway independently of c-Raf,” Oncogene, vol. 26, no. 6, pp. 813–821, 2007.
[125]
M. S. Lim, M. L. Carlson, D. K. Crockett et al., “The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways,” Blood, vol. 114, no. 8, pp. 1585–1595, 2009.
[126]
F. Vega, L. J. Medeiros, V. Leventaki et al., “Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma,” Cancer Research, vol. 66, no. 13, pp. 6589–6597, 2006.
[127]
M. Marzec, M. Kasprzycka, X. Liu et al., “Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway,” Oncogene, vol. 26, no. 38, pp. 5606–5614, 2007.
[128]
B. Magnuson, B. Ekim, D. C. Fingar, et al., “Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks,” Biochemical Journal, vol. 441, no. 1, pp. 1–21, 2012.
[129]
M. Fernandez, R. Manso, F. Bernaldez, P. Lopez, A. Martin-Duce, and S. Alemany, “Involvement of Cot activity in the proliferation of ALCL lymphoma cells,” Biochemical and Biophysical Research Communications, vol. 411, no. 4, pp. 655–660, 2011.
[130]
B. D. Manning and L. C. Cantley, “Rheb fills a GAP between TSC and TOR,” Trends in Biochemical Sciences, vol. 28, no. 11, pp. 573–576, 2003.
[131]
X. M. Ma and J. Blenis, “Molecular mechanisms of mTOR-mediated translational control,” Nature Reviews Molecular Cell Biology, vol. 10, no. 5, pp. 307–318, 2009.
[132]
O. Merkel, F. Hamacher, D. Laimer et al., “Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+ and ALK- anaplastic large-cell lymphoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 37, pp. 16228–16233, 2010.
[133]
M. Watanabe, K. Itoh, T. Togano, M. E. Kadin, T. Watanabe, and R. Horie, “Ets-1 activates overexpression of JunB and CD30 in Hodgkin's lymphoma and anaplastic large-cell lymphoma,” The American Journal of Pathology, vol. 180, no. 2, pp. 831–838, 2012.
[134]
S. Mathas, M. Hinz, I. Anagnostopoulos et al., “Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-κB,” The EMBO Journal, vol. 21, no. 15, pp. 4104–4113, 2002.
[135]
A. P. Szremska, L. Kenner, E. Weisz et al., “JunB inhibits proliferation and transformation in B-lymphoid cells,” Blood, vol. 102, no. 12, pp. 4159–4165, 2003.
[136]
G. Z. Rassidakis, A. Thomaides, C. Atwell et al., “JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis,” Modern Pathology, vol. 18, no. 10, pp. 1365–1370, 2005.
[137]
F. Y. Y. Hsu, P. B. Johnston, K. A. Burke, and Y. Zhao, “The expression of CD30 in anaplastic large cell lymphoma is regulated by nucleophosmin-anaplastic lymphoma kinase-mediated JunB level in a cell type-specific manner,” Cancer Research, vol. 66, no. 18, pp. 9002–9008, 2006.
[138]
J. D. Pearson, J. K. Lee, J. T. Bacani, R. Lai, and R. J. Ingham, “NPM-ALK and the JunB transcription factor regulate the expression of cytotoxic molecules in ALK-positive, anaplastic large cell lymphoma,” International Journal of Clinical and Experimental Pathology, vol. 4, no. 2, pp. 124–133, 2011.
[139]
J. G. Christensen, H. Y. Zou, M. E. Arango et al., “Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma,” Molecular Cancer Therapeutics, vol. 6, no. 12, pp. 3314–3322, 2007.
[140]
U. Ritter, C. Damm-Welk, U. Fuchs, R. M. Bohle, A. Borkhardt, and W. Woessmann, “Design and evaluation of chemically synthesized siRNA targeting the NPM-ALK fusion site in anaplastic large cell lymphoma (ALCL),” Oligonucleotides, vol. 13, no. 5, pp. 365–373, 2003.
[141]
S. D. Turner, D. Yeung, K. Hadfield, S. J. Cook, and D. R. Alexander, “The NPM-ALK tyrosine kinase mimics TCR signalling pathways, inducing NFAT and AP-1 by RAS-dependent mechanisms,” Cellular Signalling, vol. 19, no. 4, pp. 740–747, 2007.
[142]
C. Voena, C. Conte, C. Ambrogio et al., “The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration,” Cancer Research, vol. 67, no. 9, pp. 4278–4286, 2007.
[143]
L. Riera, E. Lasorsa, C. Ambrogio, N. Surrenti, C. Voena, and R. Chiarle, “Involvement of Grb2 adaptor protein in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated signaling and anaplastic large cell lymphoma growth,” Journal of Biological Chemistry, vol. 285, no. 34, pp. 26441–26450, 2010.
[144]
L. C. Cantley, “The phosphoinositide 3-kinase pathway,” Science, vol. 296, no. 5573, pp. 1655–1657, 2002.
[145]
P. Liu, H. Cheng, T. M. Roberts, and J. J. Zhao, “Targeting the phosphoinositide 3-kinase pathway in cancer,” Nature Reviews Drug Discovery, vol. 8, no. 8, pp. 627–644, 2009.
[146]
R. Y. Bai, T. Ouyang, C. Miething, S. W. Morris, C. Peschel, and J. Duyster, “Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway,” Blood, vol. 96, no. 13, pp. 4319–4327, 2000.
[147]
A. Slupianek, M. Nieborowska-Skorska, G. Hoser et al., “Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis,” Cancer Research, vol. 61, no. 5, pp. 2194–2199, 2001.
[148]
D. A. E. Cross, D. R. Alessi, P. Cohen, M. Andjelkovich, and B. A. Hemmings, “Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B,” Nature, vol. 378, no. 6559, pp. 785–789, 1995.
[149]
S. R. McDonnell, S. R. Hwang, V. Basrur, et al., “NPM-ALK signals through glycogen synthase kinase 3beta to promote oncogenesis,” Oncogene. In press.
[150]
A. Fernandez-Vidal, A. Mazars, E. F. Gautier, G. Prévost, B. Payrastre, and S. Manenti, “Upregulation of the CDC25A phosphatase down-stream of the NPM/ALK oncogene participates to anaplastic large cell lymphoma enhanced proliferation,” Cell Cycle, vol. 8, no. 9, pp. 1373–1379, 2009.
[151]
R. R. Singh, J. H. Cho-Vega, Y. Davuluri et al., “Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma,” Cancer Research, vol. 69, no. 6, pp. 2550–2558, 2009.
[152]
H. Zhu and H. W. Lo, “The human glioma-associated oncogene homolog 1 (GLI1) family of transcription factors in gene regulation and diseases,” Current Genomics, vol. 11, no. 4, pp. 238–245, 2010.
[153]
T. L. Gu, Z. Tothova, B. Scheijen, J. D. Griffin, D. G. Gilliland, and D. W. Sternberg, “NPM-ALK fusion kinase of anaplastic large-cell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a,” Blood, vol. 103, no. 12, pp. 4622–4629, 2004.
[154]
H. Huang and D. J. Tindall, “Dynamic FoxO transcription factors,” Journal of Cell Science, vol. 120, no. 15, pp. 2479–2487, 2007.
[155]
P. F. Dijkers, R. H. Medema, J. W. J. Lammers, L. Koenderman, and P. J. Coffer, “Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1,” Current Biology, vol. 10, no. 19, pp. 1201–1204, 2000.
[156]
P. F. Dijkers, R. H. Medema, C. Pals et al., “Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of ,” Molecular and Cellular Biology, vol. 20, no. 24, pp. 9138–9148, 2000.
[157]
A. Slupianek and T. Skorski, “NPM/ALK downregulates in a PI-3K-dependent manner,” Experimental Hematology, vol. 32, no. 12, pp. 1265–1271, 2004.
[158]
G. Z. Rassidakis, M. Feretzaki, C. Atwell et al., “Inhibition of Akt increases levels and induces cell cycle arrest in anaplastic large cell lymphoma,” Blood, vol. 105, no. 2, pp. 827–829, 2005.
[159]
D. Polgar, C. Leisser, S. Maier et al., “Truncated ALK derived from chromosomal translocation t(2;5)(p23;q35) binds to the SH3 domain of p85-PI3K,” Mutation Research, vol. 570, no. 1, pp. 9–15, 2005.
[160]
W. Wan, M. S. Albom, L. Lu et al., “Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells,” Blood, vol. 107, no. 4, pp. 1617–1623, 2006.
[161]
A. H. Uner, A. Saglam, U. Han, M. Hayran, A. Sungur, and S. Ruacan, “PTEN and p27 expression in mature T-cell and NK-cell neoplasms,” Leukemia and Lymphoma, vol. 46, no. 10, pp. 1463–1470, 2005.
[162]
S. Momose, J. I. Tamaru, H. Kishi et al., “Hyperactivated STAT3 in ALK-positive diffuse large B-cell lymphoma with clathrin-ALK fusion,” Human Pathology, vol. 40, no. 1, pp. 75–82, 2009.
[163]
Z. Chen, T. Sasaki, X. Tan et al., “Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene,” Cancer Research, vol. 70, no. 23, pp. 9827–9836, 2010.
[164]
Y. Li, X. Ye, J. Liu, J. Zha, and L. Pei, “Evaluation of eml4-alk fusion proteins in non-small cell lung cancer using small molecule inhibitors,” Neoplasia, vol. 13, no. 1, pp. 1–11, 2011.
[165]
K. Takezawa, I. Okamoto, K. Nishio, P. A. J？nne, and K. Nakagawa, “Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer,” Clinical Cancer Research, vol. 17, no. 8, pp. 2140–2148, 2011.
[166]
F. Armstrong, M. M. Duplantier, P. Trempat et al., “Differential effects of X-ALK fusion proteins on proliferation, transformation, and invasion properties of NIH3T3 cells,” Oncogene, vol. 23, no. 36, pp. 6071–6082, 2004.
[167]
S. D. Bohling, S. D. Jenson, D. K. Crockett, J. A. Schumacher, K. S. J. Elenitoba-Johnson, and M. S. Lim, “Analysis of gene expression profile of TPM3-ALK positive anaplastic large cell lymphoma reveals overlapping and unique patterns with that of NPM-ALK positive anaplastic large cell lymphoma,” Leukemia Research, vol. 32, no. 3, pp. 383–393, 2008.
