{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T19:03:51Z","timestamp":1760295831522,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2017,10,16]],"date-time":"2017-10-16T00:00:00Z","timestamp":1508112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Anaplastic large cell lymphoma expressing anaplastic lymphoma kinase (ALK+ ALCL) is a distinct subtype of non-Hodgkin lymphoma. In this review, we discuss the historical findings that led to its classification as a unique disease, despite its varied clinical presentation and histology. We discuss the molecular mechanisms underlying ALK+ ALCL pathology and the questions that remain in the field. Finally, we visit how decades of ALK+ ALCL research has yielded more precise drugs that hold promise for the future.<\/jats:p>","DOI":"10.3390\/cancers9100138","type":"journal-article","created":{"date-parts":[[2017,10,16]],"date-time":"2017-10-16T11:11:09Z","timestamp":1508152269000},"page":"138","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["From Pathology to Precision Medicine in Anaplastic Large Cell Lymphoma Expressing Anaplastic Lymphoma Kinase (ALK+ ALCL)"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3976-0608","authenticated-orcid":false,"given":"Michael","family":"Werner","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariusz","family":"Wasik","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1111\/bjh.13958","article-title":"Anaplastic large cell lymphoma in paediatric and young adult patients","volume":"173","author":"Turner","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/299065a0","article-title":"Production of a monoclonal antibody specific for hodgkin and sternberg-reed cells of Hodgkin\u2019s disease and a subset of normal lymphoid cells","volume":"299","author":"Schwab","year":"1982","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1182\/blood.V66.4.848.848","article-title":"The expression of the Hodgkin\u2019s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: Evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells","volume":"66","author":"Stein","year":"1985","journal-title":"Blood"},{"key":"ref_4","first-page":"516","article-title":"Activation antigens: New and previously defined clusters","volume":"Volume 9","author":"McMichael","year":"1987","journal-title":"Leucocyte Typing III"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/S0140-6736(88)90367-4","article-title":"Updated kiel classification for lymphomas","volume":"331","author":"Stansfeld","year":"1988","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/j.1365-2141.1989.tb06270.x","article-title":"A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma (\u2018Ki-1 lymphoma\u2019)","volume":"71","author":"Rimokh","year":"1989","journal-title":"Br. J. Haematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1126\/science.8122112","article-title":"Fusion of a kinase gene, alk, to a nucleolar protein gene, npm, in non-Hodgkin\u2019s lymphoma","volume":"263","author":"Morris","year":"1994","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1038\/sj.onc.1201062","article-title":"ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin\u2019s lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK)","volume":"14","author":"Morris","year":"1997","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/sj.onc.1200849","article-title":"Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system","volume":"14","author":"Iwahara","year":"1997","journal-title":"Oncogene"},{"key":"ref_10","first-page":"1567","article-title":"Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3","volume":"9","author":"Shiota","year":"1994","journal-title":"Oncogene"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4181","DOI":"10.1073\/pnas.93.9.4181","article-title":"Characterization of the transforming activity of p80, a hyperphosphorylated protein in a ki-1 lymphoma cell line with chromosomal translocation t(2;5)","volume":"93","author":"Fujimoto","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1128\/MCB.17.4.2312","article-title":"Role of the nucleophosmin (NPM) portion of the non-Hodgkin\u2019s lymphoma-associated npm-anaplastic lymphoma kinase fusion protein in oncogenesis","volume":"17","author":"Bischof","year":"1997","journal-title":"Mol. Cell. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1053\/j.seminoncol.2009.02.007","article-title":"Anaplastic lymphoma kinase (ALK)-induced malignancies: Novel mechanisms of cell transformation and potential therapeutic approaches","volume":"36","author":"Wasik","year":"2009","journal-title":"Semin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrc2291","article-title":"The anaplastic lymphoma kinase in the pathogenesis of cancer","volume":"8","author":"Chiarle","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_15","unstructured":"Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J., and Vardiman, J.W. (2008). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, International Agency for Research on Cancer."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1182\/blood-2016-01-643569","article-title":"The 2016 revision of the World Health Organization classification of lymphoid neoplasms","volume":"127","author":"Swerdlow","year":"2016","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5831","DOI":"10.1073\/pnas.0900912106","article-title":"Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma","volume":"106","author":"Mathas","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/leu.2008.320","article-title":"Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas","volume":"23","author":"Feldman","year":"2008","journal-title":"Leukemia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1182\/blood-2010-08-303305","article-title":"Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing","volume":"117","author":"Feldman","year":"2011","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1182\/blood-2012-03-419937","article-title":"Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas","volume":"120","author":"Vasmatzis","year":"2012","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.ccell.2015.03.006","article-title":"Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma","volume":"27","author":"Crescenzo","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9002","DOI":"10.1158\/0008-5472.CAN-05-4101","article-title":"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","volume":"66","author":"Hsu","year":"2006","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1182\/blood.V126.23.1537.1537","article-title":"Frontline treatment of CD30+ Peripheral T-cell lymphomas with brentuximab vedotin in combination with CHP: 3-year durability and survival follow-up","volume":"126","author":"Horwitz","year":"2015","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1182\/blood-2016-05-717793","article-title":"Nucleophosmin-anaplastic lymphoma kinase: The ultimate oncogene and therapeutic target","volume":"129","author":"Werner","year":"2016","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"466","DOI":"10.4049\/jimmunol.168.1.466","article-title":"Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive t\/null-cell lymphoma","volume":"168","author":"Zhang","year":"2002","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nm1249","article-title":"Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target","volume":"11","author":"Chiarle","year":"2005","journal-title":"Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Peters, S., Camidge, D.R., Shaw, A.T., Gadgeel, S., Ahn, J.S., Kim, D.-W., Ou, S.-H.I., P\u00e9rol, M., Dziadziuszko, R., and Rosell, R. (2017). Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N. Engl. J. Med.","DOI":"10.1056\/NEJMoa1704795"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1056\/NEJMc1013224","article-title":"Crizotinib in anaplastic large-cell lymphoma","volume":"364","author":"Messa","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/S1470-2045(13)70095-0","article-title":"Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: A children\u2019s oncology group phase 1 consortium study","volume":"14","author":"Lim","year":"2013","journal-title":"Lancet Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gambacorti Passerini, C., Farina, F., Stasia, A., Redaelli, S., Ceccon, M., Mologni, L., Messa, C., Guerra, L., Giudici, G., and Sala, E. (2014). Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients. J. Natl. Cancer Inst., 106.","DOI":"10.1093\/jnci\/djt378"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3215","DOI":"10.1200\/JCO.2017.73.4830","article-title":"Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: A children\u2019s oncology group study","volume":"35","author":"Mosse","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s00432-014-1589-3","article-title":"Activating mutations in alk kinase domain confer resistance to structurally unrelated ALK inhibitors in NPM-ALK-positive anaplastic large-cell lymphoma","volume":"140","author":"Zdzalik","year":"2014","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2916","DOI":"10.1158\/0008-5472.CAN-14-3437","article-title":"Evidence suggesting that discontinuous dosing of ALK kinase inhibitors may prolong control of ALK+ tumors","volume":"75","author":"Amin","year":"2015","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1158\/1541-7786.MCR-12-0569","article-title":"Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated alk inhibitors","volume":"11","author":"Ceccon","year":"2012","journal-title":"Mol. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"607","DOI":"10.7326\/L16-0037","article-title":"Nivolumab for refractory anaplastic large cell lymphoma: A case report","volume":"165","author":"Hebart","year":"2016","journal-title":"Ann. Intern. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1038\/nm.2966","article-title":"PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas","volume":"18","author":"Laimer","year":"2012","journal-title":"Nat. Med."},{"key":"ref_37","first-page":"236","article-title":"Twenty years of modelling NPM-ALK-induced lymphomagenesis","volume":"7","author":"Giuriato","year":"2014","journal-title":"Front. Biosci. (Sch. Ed.)"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1038\/onc.2016.366","article-title":"NPM-ALK phosphorylates WASp Y102 and contributes to oncogenesis of anaplastic large cell lymphoma","volume":"36","author":"Sahasrabuddhe","year":"2017","journal-title":"Oncogene"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/nsmb796","article-title":"Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation","volume":"11","author":"Peterson","year":"2004","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6581","DOI":"10.1073\/pnas.1701263114","article-title":"Functional proteogenomics reveals biomarkers and therapeutic targets in lymphomas","volume":"114","author":"Rolland","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"282","DOI":"10.2340\/00015555-1345","article-title":"Serum IL-31 levels are increased in patients with cutaneous T-cell lymphoma","volume":"92","author":"Ohmatsu","year":"2012","journal-title":"Acta Derm. Venereol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1038\/jid.2013.227","article-title":"IL-31 is produced by the malignant T-cell population in cutaneous T-Cell lymphoma and correlates with CTCL pruritus","volume":"133","author":"Singer","year":"2013","journal-title":"J. Invest. Dermatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/leu.2014.291","article-title":"The interleukin (IL)-31\/IL-31R axis contributes to tumor growth in human follicular lymphoma","volume":"29","author":"Ferretti","year":"2015","journal-title":"Leukemia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6200","DOI":"10.4049\/jimmunol.1300744","article-title":"Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM\/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming","volume":"191","author":"Marzec","year":"2013","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1021\/acschembio.5b00945","article-title":"Strategies and approaches of targeting STAT3 for cancer treatment","volume":"11","author":"Furtek","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5399","DOI":"10.1038\/sj.onc.1206849","article-title":"Inhibition of Jak3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma","volume":"22","author":"Amin","year":"2003","journal-title":"Oncogene"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1038\/sj.onc.1207398","article-title":"Identification of NPM-ALK interacting proteins by tandem mass spectrometry","volume":"23","author":"Crockett","year":"2004","journal-title":"Oncogene"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.humpath.2005.07.011","article-title":"Jak3 activation is significantly associated with ALK expression in anaplastic large cell lymphoma","volume":"36","author":"Lai","year":"2005","journal-title":"Hum. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1038\/sj.onc.1205152","article-title":"Anaplastic lymphoma kinase (ALK) activates STAT3 and protects hematopoietic cells from cell death","volume":"21","author":"Zamo","year":"2002","journal-title":"Oncogene"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1038\/labinvest.3700348","article-title":"Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3","volume":"85","author":"Marzec","year":"2005","journal-title":"Lab. Investig."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/9\/10\/138\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:47:25Z","timestamp":1760208445000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/9\/10\/138"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,16]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2017,10]]}},"alternative-id":["cancers9100138"],"URL":"https:\/\/doi.org\/10.3390\/cancers9100138","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2017,10,16]]}}}