{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T05:45:23Z","timestamp":1770529523307,"version":"3.49.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The wingless and integration site growth factor-5a (Wnt5a) is a ligand of the receptor tyrosine kinase-like orphan receptor-1 (ROR1). Because both Wnt5a and ROR1 are expressed in circulating chronic lymphocytic leukemia (CLL) cells, and because in other cell types, STAT3, which is constitutively activated in CLL, induces Wnt5a signaling, we wondered whether STAT3 induces the expression of Wnt5a in CLL cells. Sequence analysis detected four putative STAT3 binding sites in close proximity to the Wnt5a gene promoter\u2019s start codon. Chromatin immunoprecipitation and EMSA revealed that STAT3 binds to the Wnt5a gene promoter, and a luciferase assay showed that STAT3 activates the Wnt5a gene. Additionally, transfection of peripheral blood CLL cells with STAT3 short hairpin RNA downregulated Wnt5a mRNA and protein levels, suggesting that STAT3 binds to the Wnt5a gene promoter and induces the expression of Wnt5a in CLL cells. Flow cytometry and confocal microscopy determined that both Wnt5a and its receptor ROR1 are coexpressed on the surface of CLL cells, and Western immunoblotting showed an inverse correlation between Wnt5a and ROR1 protein levels, implying that, regardless of CLL cells\u2019 ROR1 levels, blocking the interaction between Wnt5a and ROR1 might be beneficial to patients with CLL. Indeed, transfection of CLL cells with Wnt5a small interfering RNA reduced Wnt5a mRNA and protein levels and significantly increased the spontaneous apoptotic rate of CLL cells. Taken together, our data unravel an autonomous STAT3-driven prosurvival circuit that provides circulating CLL cells with a microenvironment-independent survival advantage.<\/jats:p>","DOI":"10.4049\/jimmunol.1900389","type":"journal-article","created":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T20:39:10Z","timestamp":1571863150000},"page":"3078-3085","source":"Crossref","is-referenced-by-count":22,"title":["STAT3-Induced Wnt5a Provides Chronic Lymphocytic Leukemia Cells with Survival Advantage"],"prefix":"10.1093","volume":"203","author":[{"given":"Uri","family":"Rozovski","sequence":"first","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"},{"name":"Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Sackler School of Medicine, Tel Aviv University , Tel Aviv 6997801 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0195-0871","authenticated-orcid":false,"given":"Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Preetesh","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Ferrajoli","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan A","family":"Burger","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4343-5712","authenticated-orcid":false,"given":"Prithviraj","family":"Bose","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2086-6031","authenticated-orcid":false,"given":"Phillip A","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nitin","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William G","family":"Wierda","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8613-121X","authenticated-orcid":false,"given":"Orit","family":"Uziel","sequence":"additional","affiliation":[{"name":"The Felsenstein Medical Research Center, Rabin Medical Center, Sackler School of Medicine, Tel Aviv University , Tel Aviv 6997801 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9121-6450","authenticated-orcid":false,"given":"Michael J","family":"Keating","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1623-3613","authenticated-orcid":false,"given":"Zeev","family":"Estrov","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,12,1]]},"reference":[{"key":"2025030417544449700_r1","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1007\/s13238-014-0059-7","article-title":"ROR1, an embryonic protein with an emerging role in cancer biology","volume":"5","author":"Borcherding","year":"2014","journal-title":"Protein Cell"},{"key":"2025030417544449700_r2","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1002\/ijc.23587","article-title":"Ror1, a cell surface receptor tyrosine kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for therapy","volume":"123","author":"Daneshmanesh","year":"2008","journal-title":"Int. J. Cancer"},{"key":"2025030417544449700_r3","article-title":"Stat3 activates the receptor tyrosine kinase like orphan receptor-1 gene in chronic lymphocytic leukemia cells","volume":"5","author":"Li","year":"2010","journal-title":"PLoS One"},{"key":"2025030417544449700_r4","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1182\/blood-2017-12-819383","article-title":"Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1\/2 in chronic lymphocytic leukemia","volume":"132","author":"Hasan","year":"2018","journal-title":"Blood"},{"key":"2025030417544449700_r5","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.1748-1716.2011.02294.x","article-title":"Wnt5a: its signalling, functions and implication in diseases","volume":"204","author":"Kikuchi","year":"2012","journal-title":"Acta Physiol. (Oxf.)"},{"key":"2025030417544449700_r6","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1002\/jcb.21097","article-title":"Cross-talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differentiation","volume":"101","author":"Baksh","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"2025030417544449700_r7","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/jcb.21848","article-title":"Wnt5a induces homodimerization and activation of Ror2 receptor tyrosine kinase","volume":"105","author":"Liu","year":"2008","journal-title":"J. Cell. Biochem."},{"key":"2025030417544449700_r8","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1172\/JCI83535","article-title":"Wnt5a induces ROR1\/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation","volume":"126","author":"Yu","year":"2016","journal-title":"J. Clin. Invest."},{"key":"2025030417544449700_r9","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1158\/1078-0432.CCR-15-0154","article-title":"Autocrine signaling by Wnt-5a deregulates chemotaxis of leukemic cells and predicts clinical outcome in chronic lymphocytic leukemia","volume":"22","author":"Janovska","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"2025030417544449700_r10","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1182\/blood-2009-10-230060","article-title":"STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells","volume":"115","author":"Hazan-Halevy","year":"2010","journal-title":"Blood"},{"key":"2025030417544449700_r11","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1158\/1541-7786.MCR-14-0412","article-title":"Aberrant LPL expression, driven by STAT3, mediates free fatty acid metabolism in CLL cells","volume":"13","author":"Rozovski","year":"2015","journal-title":"Mol. Cancer Res."},{"key":"2025030417544449700_r12","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/1476-4598-12-50","article-title":"Signal transducer and activator of transcription (STAT)-3 regulates microRNA gene expression in chronic lymphocytic leukemia cells","volume":"12","author":"Rozovski","year":"2013","journal-title":"Mol. Cancer"},{"key":"2025030417544449700_r13","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1158\/1541-7786.MCR-10-0559","article-title":"STAT-3 activates NF-kappaB in chronic lymphocytic leukemia cells","volume":"9","author":"Liu","year":"2011","journal-title":"Mol. Cancer Res."},{"key":"2025030417544449700_r14","first-page":"273","article-title":"STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer (Review)","volume":"19","author":"Katoh","year":"2007","journal-title":"Int. J. Mol. Med."},{"key":"2025030417544449700_r15","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1007\/s00432-011-1037-6","article-title":"Down-regulation of JAK1 by RNA interference inhibits growth of the lung cancer cell line A549 and interferes with the PI3K\/mTOR pathway","volume":"137","author":"Liu","year":"2011","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"2025030417544449700_r16","doi-asserted-by":"crossref","first-page":"2931","DOI":"10.1182\/blood-2016-04-712562","article-title":"High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia","volume":"128","author":"Cui","year":"2016","journal-title":"Blood"},{"key":"2025030417544449700_r17","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1089\/jir.1997.17.121","article-title":"GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression","volume":"17","author":"Decker","year":"1997","journal-title":"J. Interferon Cytokine Res."},{"key":"2025030417544449700_r18","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0078339","article-title":"The tyrosine kinase receptor ROR1 is constitutively phosphorylated in chronic lymphocytic leukemia (CLL) cells","volume":"8","author":"Hojjat-Farsangi","year":"2013","journal-title":"PLoS One"},{"key":"2025030417544449700_r19","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/313745a0","article-title":"Autocrine growth factors and cancer","volume":"313","author":"Sporn","year":"1985","journal-title":"Nature"},{"key":"2025030417544449700_r20","doi-asserted-by":"crossref","first-page":"R63","DOI":"10.1186\/bcr1769","article-title":"Autocrine WNT signaling contributes to breast cancer cell proliferation via the canonical WNT pathway and EGFR transactivation","volume":"9","author":"Schlange","year":"2007","journal-title":"Breast Cancer Res."},{"key":"2025030417544449700_r21","doi-asserted-by":"crossref","first-page":"99","DOI":"10.3109\/03009734.2012.665097","article-title":"PDGF and PDGF receptors in glioma","volume":"117","author":"Nazarenko","year":"2012","journal-title":"Ups. J. Med. Sci."},{"key":"2025030417544449700_r22","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1158\/1541-7786.MCR-16-0291","article-title":"Constitutive phosphorylation of STAT3 by the CK2-BLNK-CD5 complex","volume":"15","author":"Rozovski","year":"2017","journal-title":"Mol. Cancer Res."},{"key":"2025030417544449700_r23","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1182\/blood-2013-01-478222","article-title":"Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia","volume":"122","author":"Ferrajoli","year":"2013","journal-title":"Blood"},{"key":"2025030417544449700_r24","doi-asserted-by":"crossref","first-page":"21268","DOI":"10.18632\/oncotarget.25066","article-title":"STAT3-activated CD36 facilitates fatty acid uptake in chronic lymphocytic leukemia cells","volume":"9","author":"Rozovski","year":"2018","journal-title":"Oncotarget"},{"key":"2025030417544449700_r25","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/leu.2015.187","article-title":"Metabolic plasticity in CLL: adaptation to the hypoxic niche","volume":"30","author":"Koczula","year":"2016","journal-title":"Leukemia"},{"key":"2025030417544449700_r26","doi-asserted-by":"crossref","first-page":"42130","DOI":"10.18632\/oncotarget.6239","article-title":"Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival","volume":"6","author":"Trimarco","year":"2015","journal-title":"Oncotarget"},{"key":"2025030417544449700_r27","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.yexcr.2003.07.006","article-title":"Wnt-1 signaling inhibits human umbilical vein endothelial cell proliferation and alters cell morphology","volume":"291","author":"Cheng","year":"2003","journal-title":"Exp. Cell Res."},{"key":"2025030417544449700_r28","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1006\/bbrc.1999.1344","article-title":"Identification of a Wnt-responsive signal transduction pathway in primary endothelial cells","volume":"263","author":"Wright","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025030417544449700_r29","article-title":"Phenotype, development, and biological function of myeloid-derived suppressor cells","volume":"5","author":"Zhao","year":"2015","journal-title":"OncoImmunology"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/203\/11\/3078\/61421273\/ji1900389.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/203\/11\/3078\/61421273\/ji1900389.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T19:29:25Z","timestamp":1741116565000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/203\/11\/3078\/7952532"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,1]]},"references-count":29,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2019,12,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1900389","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,12]]},"published":{"date-parts":[[2019,12,1]]}}}