Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy

Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase in the insulin receptor superfamily, was initially identified in constitutively activated oncogenic fusion forms – the most common being nucleophosmin-ALK – in anaplastic large-cell lymphomas, and subsequent studies have identified ALK fusions in diffuse large B-cell lymphomas, systemic histiocytosis, inflammatory myofibroblastic tumors, esophageal squamous cell carcinomas and non-small-cell lung carcinomas. More recently, genomic DNA amplification and protein overexpression, as well as activating point mutations, of ALK have been described in neuroblastomas. In addition to those cancers for which a causative role for aberrant ALK activity is well validated, more circumstantial links implicate the full-length, normal ALK receptor in the genesis of other malignancies – including glioblastoma and breast cancer – via a mechanism of receptor activation involving autocrine and/or paracrine growth loops with the reported ALK ligands, pleiotrophin and midkine. This review summarizes normal ALK biology, the confirmed and putative roles of ALK in the development of human cancers and efforts to target ALK using small-molecule kinase inhibitors.

[1]  R. Warnke,et al.  Anaplastic Large‐Cell Lymphoma , 2011 .

[2]  H. Caron,et al.  Neuroblastoma: biology, prognosis, and treatment. , 2010, Hematology/oncology clinics of North America.

[3]  J. Castillo,et al.  ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature , 2009, Journal of hematology & oncology.

[4]  Y. Ishikawa,et al.  A mouse model for EML4-ALK-positive lung cancer , 2008, Proceedings of the National Academy of Sciences.

[5]  S. Ogawa,et al.  Oncogenic mutations of ALK kinase in neuroblastoma , 2008, Nature.

[6]  Gudrun Schleiermacher,et al.  Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma , 2008, Nature.

[7]  John M. Maris,et al.  Identification of ALK as a major familial neuroblastoma predisposition gene , 2008, Nature.

[8]  J. Chan,et al.  ALK+ histiocytosis: a novel type of systemic histiocytic proliferative disorder of early infancy. , 2008, Blood.

[9]  D. Gary Gilliland,et al.  Activating mutations in ALK provide a therapeutic target in neuroblastoma , 2008, Nature.

[10]  H. Pape,et al.  The Survival-promoting Peptide Y-P30 Enhances Binding of Pleiotrophin to Syndecan-2 and -3 and Supports Its Neuritogenic Activity* , 2008, Journal of Biological Chemistry.

[11]  Rongshi Li,et al.  Development of anaplastic lymphoma kinase (ALK) small‐molecule inhibitors for cancer therapy , 2008, Medicinal research reviews.

[12]  H. Sugimura,et al.  EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. , 2008, Lung cancer.

[13]  G. Delsol,et al.  Elevated levels of PtdIns5P in NPM-ALK transformed cells: implication of PIKfyve. , 2008, Biochemical and biophysical research communications.

[14]  N. Gotoh Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins , 2008, Cancer science.

[15]  Yuki Togashi,et al.  Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. , 2008, Cancer research.

[16]  Derek Y. Chiang,et al.  EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer , 2008, Clinical Cancer Research.

[17]  Stefano A Pileri,et al.  ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. , 2008, Blood.

[18]  E. Montgomery,et al.  Inflammatory myofibroblastic tumor and low-grade myofibroblastic sarcoma: a comparative study of clinicopathologic features and further observations on the immunohistochemical profile of myofibroblasts. , 2008, Human pathology.

[19]  A. Iafrate,et al.  Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. , 2008, Cancer research.

[20]  P. Pérez-Piñera,et al.  Pleiotrophin, a multifunctional angiogenic factor: mechanisms and pathways in normal and pathological angiogenesis , 2008, Current opinion in hematology.

[21]  G. Delsol,et al.  Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas , 2008, Oncogene.

[22]  T. Utsunomiya,et al.  EML4–ALK fusion transcript is not found in gastrointestinal and breast cancers , 2008, British Journal of Cancer.

[23]  Balazs Halmos,et al.  Structure and clinical relevance of the epidermal growth factor receptor in human cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  M. Loda,et al.  Inflammatory myofibroblastic tumor of the central nervous system and its relationship to inflammatory pseudotumor. , 2008, Human pathology.

[25]  L. Medeiros,et al.  An Attractive Therapeutic Target, mTOR Pathway, in ALK+ Anaplastic Large Cell Lymphoma , 2008, Advances in anatomic pathology.

[26]  Francesca Demichelis,et al.  EML4-ALK fusion lung cancer: a rare acquired event. , 2008, Neoplasia.

[27]  F. Shepherd,et al.  Epidermal growth factor receptor inhibitors in the treatment of lung cancer: reality and hopes , 2008, Current opinion in oncology.

[28]  K. Elenitoba-Johnson,et al.  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. , 2008, Leukemia research.

[29]  Carlo Gambacorti-Passerini,et al.  Characterization of Some Molecular Mechanisms Governing Autoactivation of the Catalytic Domain of the Anaplastic Lymphoma Kinase* , 2008, Journal of Biological Chemistry.

[30]  G. V. Vande Woude,et al.  Showering c-MET-dependent cancers with drugs. , 2008, Current opinion in genetics & development.

[31]  Petr Znamenskiy,et al.  Behavioral and Neurochemical Alterations in Mice Deficient in Anaplastic Lymphoma Kinase Suggest Therapeutic Potential for Psychiatric Indications , 2008, Neuropsychopharmacology.

[32]  Yuki Togashi,et al.  EML4-ALK Fusion Is Linked to Histological Characteristics in a Subset of Lung Cancers , 2008, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[33]  Laura A. Sullivan,et al.  Global Survey of Phosphotyrosine Signaling Identifies Oncogenic Kinases in Lung Cancer , 2007, Cell.

[34]  A. Iafrate,et al.  Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling , 2007, Proceedings of the National Academy of Sciences.

[35]  P. Zimmerman,et al.  Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas. , 2007, Oncology.

[36]  T. Mathivet,et al.  In contrast to agonist monoclonal antibodies, both C-terminal truncated form and full length form of Pleiotrophin failed to activate vertebrate ALK (anaplastic lymphoma kinase)? , 2007, Cellular signalling.

[37]  Shinji Yamazaki,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 , 2007, Molecular Cancer Therapeutics.

[38]  L. Kenner,et al.  The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling. , 2007, Blood.

[39]  M. Wasik,et al.  STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression , 2007, Nature Medicine.

[40]  J. Hornick,et al.  Inflammatory myofibroblastic tumours: where are we now? , 2007, Journal of Clinical Pathology.

[41]  J. Mortimer,et al.  The receptor protein tyrosine phosphatase (RPTP)beta/zeta is expressed in different subtypes of human breast cancer. , 2007, Biochemical and biophysical research communications.

[42]  A. Villa,et al.  NPM/ALK binds and phosphorylates the RNA/DNA-binding protein PSF in anaplastic large-cell lymphoma. , 2007, Blood.

[43]  Jorge Cortes,et al.  Flying under the radar: the new wave of BCR–ABL inhibitors , 2007, Nature Reviews Drug Discovery.

[44]  Wei Zhang,et al.  Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling pathway: an alternative mechanism of receptor tyrosine kinase activation. , 2007, The Journal of biological chemistry.

[45]  K. Elenitoba-Johnson,et al.  NPM-ALK oncogenic kinase promotes cell-cycle progression through activation of JNK/cJun signaling in anaplastic large-cell lymphoma. , 2007, Blood.

[46]  R. Motzer,et al.  Treatment options in renal cell carcinoma: past, present and future. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[47]  P. Włodarski,et al.  Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway , 2007, Oncogene.

[48]  H. Aburatani,et al.  Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer , 2007, Nature.

[49]  S. Tripp,et al.  Global proteome profiling of NPM/ALK-positive anaplastic large cell lymphoma. , 2007, Experimental hematology.

[50]  C. Kuo,et al.  Vascular endothelial growth factor: biology and therapeutic applications. , 2007, The international journal of biochemistry & cell biology.

[51]  P. Pérez-Piñera,et al.  Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer. , 2007, Biochemical and biophysical research communications.

[52]  E. Papadimitriou,et al.  Pleiotrophin as a possible new target for angiogenesis-related diseases and cancer. , 2007, Recent patents on anti-cancer drug discovery.

[53]  M. Kinney,et al.  Cutaneous T-cell and NK-cell lymphomas: the WHO-EORTC classification and the increasing recognition of specialized tumor types. , 2007, American journal of clinical pathology.

[54]  T. Kuzel,et al.  Primary cutaneous CD30+ lymphoproliferative disorders: new insights into biology and therapy. , 2007, Oncology.

[55]  Shinji Yamazaki,et al.  An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. , 2007, Cancer research.

[56]  S. Mohammed,et al.  The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration. , 2007, Cancer research.

[57]  James D. Griffin,et al.  Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia , 2007, Nature Reviews Cancer.

[58]  Ravi Salgia,et al.  A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts. , 2007, Cancer research.

[59]  H. Cualing,et al.  Need for an improved molecular/genetic classification for CD30+ lymphomas involving the skin. , 2007, Cancer control : journal of the Moffitt Cancer Center.

[60]  S. Cook,et al.  The NPM-ALK tyrosine kinase mimics TCR signalling pathways, inducing NFAT and AP-1 by RAS-dependent mechanisms. , 2007, Cellular signalling.

[61]  C. Fletcher,et al.  Inflammatory Myofibroblastic Tumor: Comparison of Clinicopathologic, Histologic, and Immunohistochemical Features Including ALK Expression in Atypical and Aggressive Cases , 2007, The American journal of surgical pathology.

[62]  R. Palmer,et al.  Anterograde Jelly belly and Alk Receptor Tyrosine Kinase Signaling Mediates Retinal Axon Targeting in Drosophila , 2007, Cell.

[63]  M. Meyerson,et al.  Genome-Wide Analysis of Neuroblastomas using High-Density Single Nucleotide Polymorphism Arrays , 2007, PloS one.

[64]  Q. Zhan,et al.  Proteomic profiling of proteins dysregulted in Chinese esophageal squamous cell carcinoma , 2007, Journal of Molecular Medicine.

[65]  Joffrey L. Degoutin,et al.  ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation , 2007, FEBS letters.

[66]  Peter G. Schultz,et al.  Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK , 2007, Proceedings of the National Academy of Sciences.

[67]  P. Starostik,et al.  Remission of Philadelphia chromosome-positive central nervous system leukemia after dasatinib therapy , 2007, Leukemia & lymphoma.

[68]  R. Palmer,et al.  The bHLH transcription factor Hand is regulated by Alk in the Drosophila embryonic gut. , 2006, Biochemical and biophysical research communications.

[69]  Roberto Piva,et al.  Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and BCL2A1 as critical target genes. , 2006, The Journal of clinical investigation.

[70]  J. Larkin,et al.  Kinase inhibitors in the treatment of renal cell carcinoma. , 2006, Critical reviews in oncology/hematology.

[71]  L. Medeiros,et al.  The HSP90 inhibitor 17-AAG synergizes with doxorubicin and U0126 in anaplastic large cell lymphoma irrespective of ALK expression. , 2006, Experimental hematology.

[72]  T. Muramatsu,et al.  Midkine, a heparin‐binding growth factor, is expressed in neural precursor cells and promotes their growth , 2006, Journal of neurochemistry.

[73]  E. Montgomery,et al.  Inflammatory Myofibroblastic Tumors of the Urinary Tract: A Clinicopathologic Study of 46 Cases, Including a Malignant Example Inflammatory Fibrosarcoma and a Subset Associated With High-grade Urothelial Carcinoma , 2006, The American journal of surgical pathology.

[74]  R. Malekzadeh,et al.  Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer. , 2006, World journal of gastroenterology.

[75]  H. Joensuu Sunitinib for imatinib-resistant GIST , 2006, The Lancet.

[76]  T. Muramatsu,et al.  Neuroglycan C Is a Novel Midkine Receptor Involved in Process Elongation of Oligodendroglial Precursor-like Cells* , 2006, Journal of Biological Chemistry.

[77]  L. Scapozza,et al.  Structural insights into the ATP binding pocket of the anaplastic lymphoma kinase by site-directed mutagenesis, inhibitor binding analysis, and homology modeling. , 2006, Journal of medicinal chemistry.

[78]  R. Palmer,et al.  Characterization of the expression of the ALK receptor tyrosine kinase in mice. , 2006, Gene expression patterns : GEP.

[79]  P. Opolon,et al.  Pleiotrophin, a candidate gene for poor tumor vasculature and in vivo neuroblastoma sensitivity to irinotecan , 2006, Oncogene.

[80]  T. Asada,et al.  Possible association between nonsynonymous polymorphisms of the anaplastic lymphoma kinase (ALK) gene and schizophrenia in a Japanese population , 2006, Journal of Neural Transmission.

[81]  V. Copié,et al.  Anaplastic lymphoma kinase is dynamically expressed on subsets of motor neurons and in the peripheral nervous system , 2006, The Journal of comparative neurology.

[82]  F. Mertens,et al.  Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor , 2006, International journal of cancer.

[83]  T. Muramatsu,et al.  Midkine, a heparin-binding growth factor, produced by the host enhances metastasis of Lewis lung carcinoma cells. , 2006, Cancer letters.

[84]  B. Ruggeri,et al.  Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells. , 2006, Blood.

[85]  Rongshi Li,et al.  Design and synthesis of 5-aryl-pyridone-carboxamides as inhibitors of anaplastic lymphoma kinase. , 2006, Journal of medicinal chemistry.

[86]  A. Aigner,et al.  Ribozyme‐targeting reveals the rate‐limiting role of pleiotrophin in glioblastoma , 2005, International journal of cancer.

[87]  Dominik Wodarz,et al.  Emergence and prevention of resistance against small molecule inhibitors. , 2005, Seminars in cancer biology.

[88]  D. Rodeberg,et al.  Pediatric inflammatory myofibroblastic tumor: Anaplastic lymphoma kinase (ALK) expression and prognosis , 2005, Pediatric blood & cancer.

[89]  Hannah Al Kinases as drug discovery targets in hematologic malignancies. , 2005 .

[90]  Y. Révillon,et al.  Inflammatory myofibroblastic tumor in children: clinical review with anaplastic lymphoma kinase, Epstein-Barr virus, and human herpesvirus 8 detection analysis. , 2005, Journal of pediatric surgery.

[91]  S. Nelson,et al.  Differential Induction of Glioblastoma Migration and Growth by Two Forms of Pleiotrophin* , 2005, Journal of Biological Chemistry.

[92]  K. Christman,et al.  Pleiotrophin induces formation of functional neovasculature in vivo. , 2005, Biochemical and biophysical research communications.

[93]  C. Créminon,et al.  Activation and Inhibition of Anaplastic Lymphoma Kinase Receptor Tyrosine Kinase by Monoclonal Antibodies and Absence of Agonist Activity of Pleiotrophin* , 2005, Journal of Biological Chemistry.

[94]  J. Christensen,et al.  c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. , 2005, Cancer letters.

[95]  R. Sakai,et al.  Biological role of anaplastic lymphoma kinase in neuroblastoma. , 2005, The American journal of pathology.

[96]  R. Sakai,et al.  Domain-specific function of ShcC docking protein in neuroblastoma cells , 2005, Oncogene.

[97]  E. Sausville,et al.  Review of UCN‐01 Development: A Lesson in the Importance of Clinical Pharmacology , 2005, Journal of clinical pharmacology.

[98]  C. Rampon,et al.  New neurons in the dentate gyrus are involved in the expression of enhanced long‐term memory following environmental enrichment , 2005, The European journal of neuroscience.

[99]  T. Muramatsu,et al.  Serum midkine concentrations and gastric cancer , 2005, Cancer science.

[100]  Ping Chen,et al.  Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. , 2004, Journal of medicinal chemistry.

[101]  R. Perez-soler,et al.  Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) in non-small-cell lung cancer. , 2004, Clinical lung cancer.

[102]  M. Noda,et al.  α4β1- and α6β1-integrins are functional receptors for midkine, a heparin-binding growth factor , 2004, Journal of Cell Science.

[103]  Tetsuya Shiraishi,et al.  Identification of pleiotrophin in conditioned medium secreted from neural stem cells by SELDI-TOF and SELDI-tandem mass spectrometry. , 2004, Brain research. Developmental brain research.

[104]  Ping Chen,et al.  Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor , 2004, Science.

[105]  M. Zhen,et al.  An SCF-like ubiquitin ligase complex that controls presynaptic differentiation , 2004, Nature.

[106]  Xiong-zeng Zhu,et al.  Expression of anaplastic lymphoma kinase in soft tissue tumors: an immunohistochemical and molecular study of 249 cases. , 2004, Human pathology.

[107]  Angelo Rosolen,et al.  Ubiquitination and proteasomal degradation of nucleophosmin-anaplastic lymphoma kinase induced by 17-allylamino-demethoxygeldanamycin: role of the co-chaperone carboxyl heat shock protein 70-interacting protein. , 2004, Cancer research.

[108]  T. Muramatsu,et al.  Midkine and pleiotrophin in neural development and cancer. , 2004, Cancer letters.

[109]  Toshihiro Tanaka The International HapMap Project , 2003, Nature.

[110]  Hiroki Toda,et al.  Inflammatory Blockade Restores Adult Hippocampal Neurogenesis , 2003, Science.

[111]  J. Christensen,et al.  A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. , 2003, Cancer research.

[112]  M. Frasch,et al.  Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers , 2003, Nature.

[113]  R. Palmer,et al.  Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion , 2003, Nature.

[114]  J. Downing,et al.  ALK-positive plasmablastic B-cell lymphoma with expression of the NPM-ALK fusion transcript: report of 2 cases. , 2003, Blood.

[115]  P. Marynen,et al.  ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma. , 2003, Blood.

[116]  R. Girgert,et al.  Significance of heparin-binding growth factor expression on cells of solid pediatric tumors. , 2003, Journal of pediatric surgery.

[117]  R. Hen,et al.  Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants , 2003, Science.

[118]  Y. Yamashita,et al.  ALK+, CD30−, CD20− Large B-Cell Lymphoma Containing Anaplastic Lymphoma Kinase (ALK) Fused to Clathrin Heavy Chain Gene (CLTC) , 2003, Modern Pathology.

[119]  T. Hunter,et al.  A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster , 2003, EMBO reports.

[120]  Yohko Nakamura,et al.  Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas , 2003, British Journal of Cancer.

[121]  H. Nishino,et al.  Pleiotrophin exhibits a trophic effect on survival of dopaminergic neurons in vitro , 2003, The European journal of neuroscience.

[122]  Ming Zhou,et al.  Fusion of ALK to the Ran‐binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor , 2003, Genes, chromosomes & cancer.

[123]  Mary Hightower Erlotinib (OSI-774, Tarceva), a selective epidermal growth factor receptor tyrosine kinase inhibitor, in combination with chemotherapy for advanced non-small-cell lung cancer. , 2003, Clinical lung cancer.

[124]  D. Govender,et al.  ALK protein expression in rhabdomyosarcomas. , 2002, Histopathology.

[125]  C. Powers,et al.  Midkine Binds to Anaplastic Lymphoma Kinase (ALK) and Acts as a Growth Factor for Different Cell Types* , 2002, The Journal of Biological Chemistry.

[126]  A. Wellstein,et al.  Anti-apoptotic Signaling of Pleiotrophin through Its Receptor, Anaplastic Lymphoma Kinase* , 2002, The Journal of Biological Chemistry.

[127]  T. Muramatsu Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. , 2002, Journal of biochemistry.

[128]  W. Sanger,et al.  Expression of ALK1 and p80 in Inflammatory Myofibroblastic Tumor and Its Mesenchymal Mimics: A Study of 135 Cases , 2002, Modern Pathology.

[129]  I. Bernard-Pierrot,et al.  Dominant Negative Effectors of Heparin Affin Regulatory Peptide (HARP) Angiogenic and Transforming Activities* , 2002, The Journal of Biological Chemistry.

[130]  R. Sakai,et al.  Activation of anaplastic lymphoma kinase is responsible for hyperphosphorylation of ShcC in neuroblastoma cell lines , 2002, Oncogene.

[131]  P. Marynen,et al.  Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumor , 2002, Genes, chromosomes & cancer.

[132]  C. Sawyers,et al.  Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[133]  H. Drexler,et al.  Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines , 2002, International journal of cancer.

[134]  C. R. Pinkerton,et al.  Anaplastic large cell lymphoma in childhood: analysis of 72 patients treated on The United Kingdom Children's Cancer Study Group chemotherapy regimens , 2002, British journal of haematology.

[135]  J. Griffin,et al.  Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease , 2002, Oncogene.

[136]  C. Powers,et al.  Pleiotrophin Signaling through Anaplastic Lymphoma Kinase Is Rate-limiting for Glioblastoma Growth* , 2002, The Journal of Biological Chemistry.

[137]  M. Baccarani,et al.  Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. , 2002, Blood.

[138]  M. Baccarani,et al.  Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. , 2002, The New England journal of medicine.

[139]  M. Scott,et al.  Jelly belly A Drosophila LDL Receptor Repeat-Containing Signal Required for Mesoderm Migration and Differentiation , 2001, Cell.

[140]  S. Morris,et al.  Anaplastic Lymphoma Kinase (ALK) Expression in the Inflammatory Myofibroblastic Tumor: A Comparative Immunohistochemical Study , 2001, The American journal of surgical pathology.

[141]  Sigrid Stroobants,et al.  Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study , 2001, The Lancet.

[142]  M. Ladanyi,et al.  Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor. , 2001, The American journal of pathology.

[143]  John B. Thomas,et al.  Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo , 2001, Genes to cells : devoted to molecular & cellular mechanisms.

[144]  M. Shimizu,et al.  Anaplastic Lymphoma Kinase Expression in Inflammatory Pseudotumors , 2001, The American journal of surgical pathology.

[145]  S. Perkins,et al.  ALK1 and p80 Expression and Chromosomal Rearrangements Involving 2p23 in Inflammatory Myofibroblastic Tumor , 2001, Modern Pathology.

[146]  D. Wen,et al.  Identification of Anaplastic Lymphoma Kinase as a Receptor for the Growth Factor Pleiotrophin* , 2001, The Journal of Biological Chemistry.

[147]  T. Hunter,et al.  Oncogenic kinase signalling , 2001, Nature.

[148]  S. Morris,et al.  Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non‐hodgkin's lymphoma , 2001, British journal of haematology.

[149]  J. Coindre,et al.  ALK probe rearrangement in a t(2;11;2)(p23;p15;q31) translocation found in a prenatal myofibroblastic fibrous lesion: Toward a molecular definition of an inflammatory myofibroblastic tumor family? , 2001, Genes, chromosomes & cancer.

[150]  S. Yousem,et al.  Involvement of 2p23 in pulmonary inflammatory pseudotumors. , 2001, Human pathology.

[151]  E. Campo,et al.  Molecular Characterization of a New ALK Translocation Involving Moesin (MSN-ALK) in Anaplastic Large Cell Lymphoma , 2001, Laboratory Investigation.

[152]  J. Goldblum,et al.  Immunohistochemical analysis of anaplastic lymphoma kinase expression in deep soft tissue calcifying fibrous pseudotumor: evidence of a late sclerosing stage of inflammatory myofibroblastic tumor? , 2001, Annals of diagnostic pathology.

[153]  S. Faivre,et al.  Le ZD 1839 : « Iressa » , 2000 .

[154]  T. Pawson,et al.  The Mammalian ShcB and ShcC Phosphotyrosine Docking Proteins Function in the Maturation of Sensory and Sympathetic Neurons , 2000, Neuron.

[155]  J. Schlessinger,et al.  Cell Signaling by Receptor Tyrosine Kinases , 2000, Cell.

[156]  D. Jonas,et al.  New molecular mediators in tumor angiogenesis , 2000, Journal of cellular and molecular medicine.

[157]  P. Seeburg,et al.  Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. , 2000, Science.

[158]  P. D. Dal Cin,et al.  TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. , 2000, The American journal of pathology.

[159]  S. Pileri,et al.  Anaplastic large‐cell lymphomas of B‐cell phenotype are anaplastic lymphoma kinase (ALK) negative and belong to the spectrum of diffuse large B‐cell lymphomas , 2000, British journal of haematology.

[160]  K. Pulford,et al.  Expression of the ALK tyrosine kinase gene in neuroblastoma. , 2000, The American journal of pathology.

[161]  K. Zou,et al.  LDL receptor-related protein as a component of the midkine receptor. , 2000, Biochemical and biophysical research communications.

[162]  R. Siebert,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. , 2000, Blood.

[163]  M. Noda,et al.  Pleiotrophin signals increased tyrosine phosphorylation of β-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase β/ζ , 2000 .

[164]  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. , 2000, Cancer research.

[165]  E. Campo,et al.  Lymphomas expressing ALK fusion protein(s) other than NPM-ALK. , 1999, Blood.

[166]  K K Matthay,et al.  Treatment of High-Risk Neuroblastoma with Intensive Chemotherapy, Radiotherapy, Autologous Bone Marrow Transplantation, and 13-cis-Retinoic Acid , 1999 .

[167]  A. Rosenwald,et al.  t(1;2)(q21;p23) and t(2;3)(p23;q21): two novel variant translocations of the t(2;5)(p23;q35) in anaplastic large cell lymphoma. , 1999, Blood.

[168]  C. Griffin,et al.  Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. , 1999, Cancer research.

[169]  A. Rosenwald,et al.  Biochemical detection of novel anaplastic lymphoma kinase proteins in tissue sections of anaplastic large cell lymphoma. , 1999, The American journal of pathology.

[170]  T. Greiner,et al.  Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. , 1999, Blood.

[171]  M. Noda,et al.  A receptor-like protein-tyrosine phosphatase PTPzeta/RPTPbeta binds a heparin-binding growth factor midkine. Involvement of arginine 78 of midkine in the high affinity binding to PTPzeta. , 1999, The Journal of biological chemistry.

[172]  S. Pileri,et al.  ALK+ lymphoma: clinico-pathological findings and outcome. , 1999, Blood.

[173]  S. Morris,et al.  Nucleophosmin-Anaplastic Lymphoma Kinase of Large-Cell Anaplastic Lymphoma Is a Constitutively Active Tyrosine Kinase That Utilizes Phospholipase C-γ To Mediate Its Mitogenicity , 1998, Molecular and Cellular Biology.

[174]  G. Leverger,et al.  Anaplastic Large-Cell Lymphoma in Children : Analysis of 82 Patients Enrolled in Two Consecutive Studies of the French Society of Pediatric Oncology , 1998 .

[175]  S. Pileri,et al.  ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum. , 1998, The American journal of pathology.

[176]  S. Morris,et al.  The t(2;5) in human lymphomas. , 1998, Leukemia & lymphoma.

[177]  S. Pileri,et al.  ALK-positive lymphoma: a single disease with a broad spectrum of morphology. , 1998, Blood.

[178]  K. Pulford,et al.  Nucleolar localization of the nucleophosmin-anaplastic lymphoma kinase is not required for malignant transformation. , 1998, Cancer research.

[179]  K. Kolibaba,et al.  Protein tyrosine kinases and cancer. , 1997, Biochimica et biophysica acta.

[180]  Y. Tsukahara,et al.  A Novel Go-mediated Phototransduction Cascade in Scallop Visual Cells* , 1997, The Journal of Biological Chemistry.

[181]  C. Naeve,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) , 1997, Oncogene.

[182]  S. Donnini,et al.  An angiogenic role for the neurokines midkine and pleiotrophin in tumorigenesis. , 1997, Cancer research.

[183]  S. Kojima,et al.  Dimerization of Midkine by Tissue Transglutaminase and Its Functional Implication* , 1997, The Journal of Biological Chemistry.

[184]  K. Pulford,et al.  Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis , 1997, Molecular and cellular biology.

[185]  P. Brousset,et al.  A new subtype of large B-cell lymphoma expressing the ALK kinase and lacking the 2; 5 translocation. , 1997, Blood.

[186]  K. Pulford,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. , 1997, Blood.

[187]  T. Arakawa,et al.  Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system , 1997, Oncogene.

[188]  A. Wellstein,et al.  Melanoma angiogenesis and metastasis modulated by ribozyme targeting of the secreted growth factor pleiotrophin. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[189]  A. Wellstein,et al.  Human trophoblast and choriocarcinoma expression of the growth factor pleiotrophin attributable to germ-line insertion of an endogenous retrovirus. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[190]  T. Shintani,et al.  6B4 Proteoglycan/Phosphacan, an Extracellular Variant of Receptor-like Protein-tyrosine Phosphatase ζ/RPTPβ, Binds Pleiotrophin/Heparin-binding Growth-associated Molecule (HB-GAM)* , 1996, The Journal of Biological Chemistry.

[191]  A. Harris,et al.  The angiogenic factor midkine is expressed in bladder cancer, and overexpression correlates with a poor outcome in patients with invasive cancers. , 1996, Cancer research.

[192]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[193]  H. Satoh,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). , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[194]  M. Barbacid Structural and Functional Properties of the TRK Family of Neurotrophin Receptors , 1995, Annals of the New York Academy of Sciences.

[195]  J. Milbrandt,et al.  Differential expression of pleiotrophin and midkine in advanced neuroblastomas. , 1995, Cancer research.

[196]  S. Morris,et al.  Clinicopathologic features and treatment outcome of children with large-cell lymphoma and the t(2;5)(p23;q35). , 1994, Blood.

[197]  C. Pedraza,et al.  Mapping and characterization of a retinoic acid-responsive enhancer of midkine, a novel heparin-binding growth/differentiation factor with neurotrophic activity. , 1994, Journal of biochemistry.

[198]  H. Satoh,et al.  Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3. , 1994, Oncogene.

[199]  D. Carey,et al.  Isolation of a neuronal cell surface receptor of heparin binding growth-associated molecule (HB-GAM). Identification as N-syndecan (syndecan-3). , 1994, The Journal of biological chemistry.

[200]  D N Shapiro,et al.  Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. , 1994, Science.

[201]  T. Deuel,et al.  Pleiotrophin transforms NIH 3T3 cells and induces tumors in nude mice. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[202]  A. Wellstein,et al.  Pleiotrophin stimulates fibroblasts and endothelial and epithelial cells and is expressed in human cancer. , 1992, The Journal of biological chemistry.

[203]  H. Rauvala,et al.  Secretion and biological activities of heparin-binding growth-associated molecule. Neurite outgrowth-promoting and mitogenic actions of the recombinant and tissue-derived protein. , 1992, The Journal of biological chemistry.

[204]  A. Wellstein,et al.  A heparin-binding growth factor secreted from breast cancer cells homologous to a developmentally regulated cytokine. , 1992, The Journal of biological chemistry.

[205]  M. Watson,et al.  Cloning and expression of a developmentally regulated protein that induces mitogenic and neurite outgrowth activity. , 1990, Science.

[206]  R. Larson,et al.  Morphology in Ki‐1 (CD30)‐Positive Non Hodgkin's Lymphoma Is Correlated with Clinical Features and the Presence of a Unique Chromosomal Abnormality, t(2;5)(p23;q35) , 1990, The American journal of surgical pathology.

[207]  R. Huang,et al.  A retinoic acid responsive gene MK found in the teratocarcinoma system is expressed in spatially and temporally controlled manner during mouse embryogenesis , 1990, The Journal of cell biology.

[208]  R. Warnke,et al.  CD30‐positive large cell lymphomas (‘Ki‐1 lymphoma’) are associated with a chromosomal translocation involving 5q35 , 1990, British journal of haematology.

[209]  R. Larson,et al.  The t(2;5)(p23;q35): a recurring chromosomal abnormality in Ki-1-positive anaplastic large cell lymphoma. , 1989, Leukemia.

[210]  M. Sasaki,et al.  A novel translocation, t(2;5)(p23;q35), in childhood phagocytic large T-cell lymphoma mimicking malignant histiocytosis. , 1989, Blood.

[211]  F. Berger,et al.  A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma (‘Ki‐1 lymphoma') , 1989, British journal of haematology.

[212]  R. Meagher,et al.  Divergence and differential expression of soybean actin genes. , 1985, The EMBO journal.

[213]  L. Shun An Orally Available Small-Molecule Inhibitor of c-Met,PF-2341066,Exhibits Cytoreductive Antitumor Efficacy through Antiproliferative and Antiangiogenic Mechanisms , 2010 .

[214]  R. Reid,et al.  Gastrointestinal stromal tumors (GIST): C-kit mutations, CD117 expression, differential diagnosis and targeted cancer therapy with imatinib , 2009, Pathology Oncology Research.

[215]  Roberto Piva,et al.  The anaplastic lymphoma kinase in the pathogenesis of cancer , 2008, Nature Reviews Cancer.

[216]  Mindy I. Davis,et al.  A quantitative analysis of kinase inhibitor selectivity , 2008, Nature Biotechnology.

[217]  D. Ilson,et al.  Targeted agents and esophageal cancer--the next step? , 2007, Seminars in Radiation Oncology.

[218]  L. Scapozza,et al.  An enzyme-linked immunosorbent assay to screen for inhibitors of the oncogenic anaplastic lymphoma kinase. , 2005, Haematologica.

[219]  A. Birve,et al.  Miple1 and miple2 encode a family of MK/PTN homologues in Drosophila melanogaster , 2005, Development Genes and Evolution.

[220]  A. Hannah Kinases as drug discovery targets in hematologic malignancies. , 2005, Current molecular medicine.

[221]  K. Pulford,et al.  Antibody techniques used in the study of anaplastic lymphoma kinase-positive ALCL. , 2005, Methods in molecular medicine.

[222]  R. Gascoyne,et al.  ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of six cases , 2003 .

[223]  F. Gannon Educate or communicate? | Ring out the old, ring in the new , 2003 .

[224]  C. Shao,et al.  [Significance of ALK gene expression in neoplasms and normal tissues]. , 2002, Ai zheng = Aizheng = Chinese journal of cancer.

[225]  K. Pulford,et al.  Model of inhibition of the NPM-ALK kinase activity by herbimycin A. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[226]  J. Baselga,et al.  Targeting epidermal growth factor receptor in lung cancer , 2002, Current oncology reports.

[227]  G. Delsol,et al.  Relapses of childhood anaplastic large-cell lymphoma: treatment results in a series of 41 children--a report from the French Society of Pediatric Oncology. , 2000, Annals of oncology : official journal of the European Society for Medical Oncology.

[228]  E. Raymond,et al.  [Zd 1839 "Iressa"]. , 2000, Bulletin du cancer.

[229]  M. Kadin,et al.  The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation. , 1999, American journal of clinical pathology.

[230]  T. Meyer,et al.  Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. , 1996, Cancer research.

[231]  S. Shurtleff,et al.  Localization of the murine homolog of the anaplastic lymphoma kinase (AlK) gene on mouse chromosome 17. , 1995, Cytogenetics and cell genetics.

[232]  D N Shapiro,et al.  Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. , 1994, Science.

[233]  W. Fantl,et al.  Signalling by receptor tyrosine kinases. , 1993, Annual review of biochemistry.