{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T14:45:38Z","timestamp":1790433938716,"version":"4.1.0"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T00:00:00Z","timestamp":1593129600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T00:00:00Z","timestamp":1593129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma subtype arising from na\u00efve B cells. Although novel therapeutics have improved patient prognosis, drug resistance remains a key problem. Here, we show that the SRC-family tyrosine kinase hematopoietic cell kinase (HCK), which is primarily expressed in the hematopoietic lineage but not in mature B cells, is aberrantly expressed in MCL, and that high expression of HCK is associated with inferior prognosis of MCL patients. HCK expression is controlled by the toll-like receptor (TLR) adaptor protein MYD88 and can be enhanced by TLR agonists in MCL cell lines and primary MCL. In line with this, primary MCL with high HCK expression are enriched for a TLR-signaling pathway gene set. Silencing of HCK expression results in cell cycle arrest and apoptosis. Furthermore, HCK controls integrin-mediated adhesion of MCL cells to extracellular matrix and stromal cells. Taken together, our data indicate that TLR\/MYD88-controlled aberrant expression of HCK plays a critical role in MCL proliferation and survival as well as in retention of the malignant cells in the growth- and survival-supporting lymphoid organ microenvironment, thereby contributing to lymphomagenesis. These novel insights provide a strong rationale for therapeutic targeting of HCK in MCL.<\/jats:p>","DOI":"10.1038\/s41375-020-0934-6","type":"journal-article","created":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T12:33:08Z","timestamp":1593174788000},"page":"881-886","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Identification of the SRC-family tyrosine kinase HCK as a therapeutic target in mantle cell lymphoma"],"prefix":"10.1038","volume":"35","author":[{"given":"Hildo C.","family":"Lantermans","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marthe","family":"Minderman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke","family":"Kuil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Jos\u00e9","family":"Kersten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven T.","family":"Pals","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3135-5109","authenticated-orcid":false,"given":"Marcel","family":"Spaargaren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,26]]},"reference":[{"key":"934_CR1","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1182\/blood-2015-10-673145","volume":"127","author":"P Martin","year":"2016","unstructured":"Martin P, Maddocks K, Leonard JP, Ruan J, Goy A, Wagner-Johnston N, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127:1559\u201363.","journal-title":"Blood."},{"key":"934_CR2","doi-asserted-by":"publisher","first-page":"2276","DOI":"10.1128\/MCB.7.6.2276","volume":"7","author":"SF Ziegler","year":"1987","unstructured":"Ziegler SF, Marth JD, Lewis DB, Perlmutter RM. Novel protein-tyrosine kinase gene (hck) preferentially expressed in cells of hematopoietic origin. Mol Cell Biol. 1987;7:2276\u201385.","journal-title":"Mol Cell Biol"},{"key":"934_CR3","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1006\/bbrc.1999.1379","volume":"264","author":"A El-Shazly","year":"1999","unstructured":"El-Shazly A, Yamaguchi N, Masuyama K, Suda T, Ishikawa T. Novel association of the Src family kinases, Hck and c-Fgr, with CCR3 receptor stimulation: A possible mechanism for eotaxin-induced human eosinophil chemotaxis. Biochem Bioph Res Co. 1999;264:163\u201370.","journal-title":"Biochem Bioph Res Co"},{"key":"934_CR4","doi-asserted-by":"publisher","first-page":"14615","DOI":"10.1074\/jbc.275.19.14615","volume":"275","author":"G Scholz","year":"2000","unstructured":"Scholz G, Cartledge K, Dunn AR. Hck enhances the adherence of lipopolysaccharide-stimulated macrophages via Cbl and phosphatidylinositol 3-kinase. J Biol Chem. 2000;275:14615\u201323.","journal-title":"J Biol Chem"},{"key":"934_CR5","doi-asserted-by":"publisher","first-page":"21658","DOI":"10.1074\/jbc.M305783200","volume":"279","author":"K Podar","year":"2004","unstructured":"Podar K, Mostoslavsky G, Sattler M, Tai YT, Hayashi T, Catley LP, et al. Critical role for hematopoietic cell kinase (Hck)-mediated phosphorylation of Gab1 and Gab2 docking proteins in interleukin 6-induced proliferation and survival of multiple myeloma cells. J Biol Chem. 2004;279:21658\u201365.","journal-title":"J Biol Chem"},{"key":"934_CR6","doi-asserted-by":"publisher","first-page":"1857","DOI":"10.1093\/carcin\/bgp206","volume":"30","author":"T Kubo","year":"2009","unstructured":"Kubo T, Kuroda Y, Shimizu H, Kokubu A, Okada N, Hosoda F, et al. Resequencing and copy number analysis of the human tyrosine kinase gene family in poorly differentiated gastric cancer. Carcinogenesis 2009;30:1857\u201364.","journal-title":"Carcinogenesis"},{"key":"934_CR7","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.bbadis.2016.11.013","volume":"1863","author":"FM Roversi","year":"2017","unstructured":"Roversi FM, Pericole FV, Machado-Neto JA, da Silva Santos Duarte A, Longhini AL, Corrocher FA, et al. Hematopoietic cell kinase (HCK) is a potential therapeutic target for dysplastic and leukemic cells due to integration of erythropoietin\/PI3K pathway and regulation of erythropoiesis: HCK in erythropoietin\/PI3K pathway. Biochim Biophys Acta Mol Basis Dis. 2017;1863:450\u201361.","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"934_CR8","doi-asserted-by":"publisher","first-page":"3237","DOI":"10.1182\/blood-2016-01-695098","volume":"127","author":"G Yang","year":"2016","unstructured":"Yang G, Buhrlage SJ, Tan L, Liu X, Chen J, Xu L, et al. HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib. Blood. 2016;127:3237\u201352.","journal-title":"Blood."},{"key":"934_CR9","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1002\/hon.2251","volume":"35","author":"A Akhter","year":"2017","unstructured":"Akhter A, Street L, Ghosh S, Burns BF, Elyamany G, Shabani-Rad MT, et al. Concomitant high expression of Toll-like receptor (TLR) and B-cell receptor (BCR) signalling molecules has clinical implications in mantle cell lymphoma. Hematol Oncol. 2017;35:79\u201386.","journal-title":"Hematol Oncol"},{"key":"934_CR10","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1002\/cncr.27792","volume":"119","author":"L Wang","year":"2013","unstructured":"Wang L, Zhao Y, Qian J, Sun L, Lu Y, Li H, et al. Toll-like receptor-4 signaling in mantle cell lymphoma: effects on tumor growth and immune evasion. Cancer. 2013;119:782\u201391.","journal-title":"Cancer."},{"key":"934_CR11","doi-asserted-by":"publisher","first-page":"e0153823","DOI":"10.1371\/journal.pone.0153823","volume":"11","author":"K Mastorci","year":"2016","unstructured":"Mastorci K, Muraro E, Pasini E, Furlan C, Sigalotti L, Cinco M, et al. Toll-like receptor 1\/2 and 5 ligands enhance the expression of cyclin D1 and D3 and induce proliferation in mantle cell lymphoma. PLoS One 2016;11:e0153823.","journal-title":"PLoS One"},{"key":"934_CR12","doi-asserted-by":"publisher","first-page":"2412","DOI":"10.1182\/blood-2013-02-482125","volume":"122","author":"BY Chang","year":"2013","unstructured":"Chang BY, Francesco M, De Rooij MF, Magadala P, Steggerda SM, Huang MM, et al. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013;122:2412\u201324.","journal-title":"Blood."},{"key":"934_CR13","doi-asserted-by":"publisher","first-page":"2306","DOI":"10.1182\/blood-2014-12-619163","volume":"125","author":"MF de Rooij","year":"2015","unstructured":"de Rooij MF, Kuil A, Kater AP, Kersten MJ, Pals ST, Spaargaren M. Ibrutinib and idelalisib synergistically target BCR-controlled adhesion in MCL and CLL: a rationale for combination therapy. Blood. 2015;125:2306\u20139.","journal-title":"Blood."},{"key":"934_CR14","doi-asserted-by":"publisher","first-page":"2590","DOI":"10.1182\/blood-2011-11-390989","volume":"119","author":"MF de Rooij","year":"2012","unstructured":"de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119:2590\u20134.","journal-title":"Blood."},{"key":"934_CR15","doi-asserted-by":"publisher","first-page":"181ra52","DOI":"10.1126\/scitranslmed.3004387","volume":"5","author":"Y Saito","year":"2013","unstructured":"Saito Y, Yuki H, Kuratani M, Hashizume Y, Takagi S, Honma T, et al. A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo. Sci Transl Med. 2013;5:181ra52.","journal-title":"Sci Transl Med"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/s41375-020-0934-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41375-020-0934-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41375-020-0934-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T21:41:20Z","timestamp":1684618880000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-020-0934-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,26]]},"references-count":15,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["934"],"URL":"https:\/\/doi.org\/10.1038\/s41375-020-0934-6","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,26]]},"assertion":[{"value":"25 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 May 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 June 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 June 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}