{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T15:47:56Z","timestamp":1781452076948,"version":"3.54.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2019,10,4]],"date-time":"2019-10-04T00:00:00Z","timestamp":1570147200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,10,4]],"date-time":"2019-10-04T00:00:00Z","timestamp":1570147200000},"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":["Oncogene"],"published-print":{"date-parts":[[2020,1,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n              <jats:p>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis in patients with resistant or relapsed disease. Although NOTCH is a known driver in T-ALL, its clinical inhibition has significant limitations. Our previous studies suggested that NRARP, a negative regulator of Notch signaling, could have a suppressive role in T-ALL. Here, we report that NRARP levels are significantly increased in primary T-ALL cells suggesting that NRARP is not sufficient to block NOTCH oncogenic signals. Interestingly, although NRARP overexpression blocks NOTCH1 signaling and delays the proliferation of T-ALL cells that display high levels of Notch1 signaling, it promotes the expansion of T-ALL cells with lower levels of Notch1 activity. We found that NRARP interacts with lymphoid enhancer-binding factor 1 (LEF1) and potentiates Wnt signaling in T-ALL cells with low levels of Notch. Together these results indicate that NRARP plays a dual role in T-ALL pathogenesis, regulating both Notch and Wnt pathways, with opposite functional effects depending on Notch activity. Consistent with this hypothesis, mice transplanted with T-cells co-expressing NOTCH1 and NRARP develop leukemia later than mice transplanted with T-NOTCH1 cells. Importantly, mice transplanted with T-cells overexpressing NRARP alone developed leukemia with similar kinetics to those transplanted with T-NOTCH1 cells. Our findings uncover a role for NRARP in T-ALL pathogenesis and indicate that Notch inhibition may be detrimental for patients with low levels of Notch signaling, which would likely benefit from the use of Wnt signaling inhibitors. Importantly, our findings may extend to other cancers where Notch and Wnt play a role.<\/jats:p>","DOI":"10.1038\/s41388-019-1042-9","type":"journal-article","created":{"date-parts":[[2019,10,4]],"date-time":"2019-10-04T18:04:37Z","timestamp":1570212277000},"page":"975-986","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["NRARP displays either pro- or anti-tumoral roles in T-cell acute lymphoblastic leukemia depending on Notch and Wnt signaling"],"prefix":"10.1038","volume":"39","author":[{"given":"In\u00eas","family":"Pinto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mafalda","family":"Duque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Gon\u00e7alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Padma","family":"Akkapeddi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana L.","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Cabrita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Andr\u00e9s","family":"Yunes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott K.","family":"Durum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4826-8976","authenticated-orcid":false,"given":"Jo\u00e3o T.","family":"Barata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9206-1964","authenticated-orcid":false,"given":"Rita","family":"Fragoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,4]]},"reference":[{"key":"1042_CR1","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1056\/NEJMra023001","volume":"350","author":"CH Pui","year":"2004","unstructured":"Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. New Engl J Med. 2004;350:1535\u201348.","journal-title":"New Engl J Med"},{"key":"1042_CR2","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1007\/s11899-009-0024-3","volume":"4","author":"MA Smith","year":"2009","unstructured":"Smith MA. Update on developmental therapeutics for acute lymphoblastic leukemia. Curr Hematol Malig Rep 2009;4:175\u201382.","journal-title":"Curr Hematol Malig Rep"},{"key":"1042_CR3","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1007\/s11899-009-0021-6","volume":"4","author":"A Fullmer","year":"2009","unstructured":"Fullmer A, O\u2019Brien S, Kantarjian H, Jabbour E. Novel therapies for relapsed acute lymphoblastic leukemia. Curr Hematol Malig Rep. 2009;4:148\u201356.","journal-title":"Curr Hematol Malig Rep"},{"key":"1042_CR4","doi-asserted-by":"publisher","first-page":"170","DOI":"10.3389\/fonc.2014.00170","volume":"4","author":"G Roti","year":"2014","unstructured":"Roti G, Stegmaier K. New Approaches to Target T-ALL. Front Oncol 2014;4:170.","journal-title":"Front Oncol"},{"key":"1042_CR5","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1126\/science.1102160","volume":"306","author":"AP Weng","year":"2004","unstructured":"Weng AP, Ferrando AA, Lee W, Morris JPt, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306:269\u201371.","journal-title":"Science"},{"key":"1042_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2015.80","volume":"5","author":"C Papayannidis","year":"2015","unstructured":"Papayannidis C, DeAngelo DJ, Stock W, Huang B, Shaik MN, Cesari R, et al. A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Blood Cancer J 2015;5:e350.","journal-title":"Blood Cancer J"},{"key":"1042_CR7","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nrd4252","volume":"13","author":"ER Andersson","year":"2014","unstructured":"Andersson ER, Lendahl U. Therapeutic modulation of Notch signalling-are we there yet? Nat Rev Drug Discov. 2014;13:357\u201378.","journal-title":"Nat Rev Drug Discov"},{"key":"1042_CR8","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1006\/dbio.2001.0408","volume":"238","author":"LT Krebs","year":"2001","unstructured":"Krebs LT, Deftos ML, Bevan MJ, Gridley T. The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway. Dev Biol. 2001;238:110\u20139.","journal-title":"Dev Biol"},{"key":"1042_CR9","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/S0925-4773(01)00570-6","volume":"110","author":"K Lahaye","year":"2002","unstructured":"Lahaye K, Kricha S, Bellefroid EJ. XNAP, a conserved ankyrin repeat-containing protein with a role in the Notch pathway during Xenopus primary neurogenesis. Mech Dev 2002;110:113\u201324.","journal-title":"Mech Dev"},{"key":"1042_CR10","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.1101\/gad.908101","volume":"15","author":"E Lamar","year":"2001","unstructured":"Lamar E, Deblandre G, Wettstein D, Gawantka V, Pollet N, Niehrs C, et al. Nrarp is a novel intracellular component of the Notch signaling pathway. Genes Dev. 2001;15:1885\u201399.","journal-title":"Genes Dev"},{"key":"1042_CR11","doi-asserted-by":"publisher","first-page":"2988","DOI":"10.1182\/blood-2008-06-164871","volume":"113","author":"I Van de Walle","year":"2009","unstructured":"Van de Walle I, De Smet G, De Smedt M, Vandekerckhove B, Leclercq G, Plum J, et al. An early decrease in Notch activation is required for human TCR-alphabeta lineage differentiation at the expense of TCR-gammadelta T cells. Blood 2009;113:2988\u201398.","journal-title":"Blood"},{"key":"1042_CR12","doi-asserted-by":"publisher","first-page":"5834","DOI":"10.4049\/jimmunol.170.12.5834","volume":"170","author":"TJ Yun","year":"2003","unstructured":"Yun TJ, Bevan MJ. Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development. J Immunol 2003;170:5834\u201341.","journal-title":"J Immunol"},{"key":"1042_CR13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002855","volume":"8","author":"R Fragoso","year":"2012","unstructured":"Fragoso R, Mao T, Wang S, Schaffert S, Gong X, Yue S, et al. Modulating the strength and threshold of NOTCH oncogenic signals by mir-181a-1\/b-1. PLoS Genet. 2012;8:e1002855.","journal-title":"PLoS Genet"},{"key":"1042_CR14","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1038\/ncb1311","volume":"7","author":"T Ishitani","year":"2005","unstructured":"Ishitani T, Matsumoto K, Chitnis AB, Itoh M. Nrarp functions to modulate neural-crest-cell differentiation by regulating LEF1 protein stability. Nat Cell Biol. 2005;7:1106\u201312.","journal-title":"Nat Cell Biol"},{"key":"1042_CR15","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.devcel.2008.12.009","volume":"16","author":"LK Phng","year":"2009","unstructured":"Phng LK, Potente M, Leslie JD, Babbage J, Nyqvist D, Lobov I, et al. Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis. Dev Cell 2009;16:70\u201382.","journal-title":"Dev Cell"},{"key":"1042_CR16","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1126\/science.281.5382.1509","volume":"281","author":"TC He","year":"1998","unstructured":"He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, et al. Identification of c-MYC as a target of the APC pathway. Science. 1998;281:1509\u201312.","journal-title":"Science"},{"key":"1042_CR17","doi-asserted-by":"crossref","first-page":"33972","DOI":"10.18632\/oncotarget.15687","volume":"8","author":"S Shang","year":"2017","unstructured":"Shang S, Hua F, Hu ZW. The regulation of beta-catenin activity and function in cancer: therapeutic opportunities. Oncotarget 2017;8:33972\u201389.","journal-title":"Oncotarget"},{"key":"1042_CR18","doi-asserted-by":"publisher","first-page":"2303","DOI":"10.1158\/1535-7163.MCT-13-1005","volume":"13","author":"MD Arensman","year":"2014","unstructured":"Arensman MD, Telesca D, Lay AR, Kershaw KM, Wu N, Donahue TR, et al. The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth. Mol Cancer Ther 2014;13:2303\u201314.","journal-title":"Mol Cancer Ther"},{"key":"1042_CR19","doi-asserted-by":"publisher","first-page":"12682","DOI":"10.1073\/pnas.0404875101","volume":"101","author":"KH Emami","year":"2004","unstructured":"Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, et al. A small molecule inhibitor of beta-catenin\/CREB-binding protein transcription [corrected]. PNAS. 2004;101:12682\u20137.","journal-title":"PNAS"},{"key":"1042_CR20","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/s10059-009-0001-7","volume":"27","author":"YH Jin","year":"2009","unstructured":"Jin YH, Kim H, Oh M, Ki H, Kim K. Regulation of Notch1\/NICD and Hes1 expressions by GSK-3alpha\/beta. Mol cells 2009;27:15\u20139.","journal-title":"Mol cells"},{"key":"1042_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1006\/dbio.2001.0566","volume":"244","author":"M van Noort","year":"2002","unstructured":"van Noort M, Clevers H. TCF transcription factors, mediators of Wnt-signaling in development and cancer. Dev Biol. 2002;244:1\u20138.","journal-title":"Dev Biol"},{"key":"1042_CR22","first-page":"53","volume":"28","author":"K Hovanes","year":"2001","unstructured":"Hovanes K, Li TW, Munguia JE, Truong T, Milovanovic T, Lawrence Marsh J, et al. Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat Genet. 2001;28:53\u20137.","journal-title":"Nat Genet"},{"key":"1042_CR23","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1093\/abbs\/37.3.173","volume":"37","author":"W Wang","year":"2005","unstructured":"Wang W, Ji P, Steffen B, Metzger R, Schneider PM, Halfter H, et al. Alterations of lymphoid enhancer factor-1 isoform expression in solid tumors and acute leukemias. Acta Biochim Biophy Sin. 2005;37:173\u201380.","journal-title":"Acta Biochim Biophy Sin"},{"key":"1042_CR24","doi-asserted-by":"publisher","first-page":"221","DOI":"10.18388\/abp.2001_5129","volume":"48","author":"A Kobielak","year":"2001","unstructured":"Kobielak A, Kobielak K, Trzeciak WH. A novel isoform of human lymphoid enhancer-binding factor-1 (LEF-1) gene transcript encodes a protein devoid of HMG domain and nuclear localization signal. Acta Biochim Pol. 2001;48:221\u20136.","journal-title":"Acta Biochim Pol"},{"key":"1042_CR25","doi-asserted-by":"publisher","first-page":"2728","DOI":"10.1080\/10428194.2017.1300896","volume":"58","author":"B Squiban","year":"2017","unstructured":"Squiban B, Ahmed ST, Frazer JK. Creation of a human T-ALL cell line online database. Leuk Lymphoma. 2017;58:2728\u201330.","journal-title":"Leuk Lymphoma"},{"key":"1042_CR26","doi-asserted-by":"publisher","first-page":"6077","DOI":"10.1038\/onc.2016.133","volume":"35","author":"P Bernasconi-Elias","year":"2016","unstructured":"Bernasconi-Elias P, Hu T, Jenkins D, Firestone B, Gans S, Kurth E, et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 2016;35:6077\u201386.","journal-title":"Oncogene"},{"key":"1042_CR27","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1038\/ng.924","volume":"43","author":"PP Zenatti","year":"2011","unstructured":"Zenatti PP, Ribeiro D, Li W, Zuurbier L, Silva MC, Paganin M, et al. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet. 2011;43:932\u20139.","journal-title":"Nat Genet"},{"key":"1042_CR28","doi-asserted-by":"publisher","first-page":"674","DOI":"10.3324\/haematol.2009.011999","volume":"95","author":"A Silva","year":"2010","unstructured":"Silva A, Jotta PY, Silveira AB, Ribeiro D, Brandalise SR, Yunes JA, et al. Regulation of PTEN by CK2 and Notch1 in primary T-cell acute lymphoblastic leukemia: rationale for combined use of CK2- and gamma-secretase inhibitors. Haematologica 2010;95:674\u20138.","journal-title":"Haematologica"},{"key":"1042_CR29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0125429","volume":"10","author":"X Guo","year":"2015","unstructured":"Guo X, Zhang R, Liu J, Li M, Song C, Dovat S, et al. Characterization of LEF1 High Expression and Novel Mutations in Adult Acute Lymphoblastic Leukemia. PLoS One. 2015;10:e0125429.","journal-title":"PLoS One"},{"key":"1042_CR30","doi-asserted-by":"publisher","first-page":"2650","DOI":"10.1182\/blood-2007-04-084202","volume":"110","author":"C Spaulding","year":"2007","unstructured":"Spaulding C, Reschly EJ, Zagort DE, Yashiro-Ohtani Y, Beverly LJ, Capobianco A, et al. Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas. Blood 2007;110:2650\u20138.","journal-title":"Blood"},{"key":"1042_CR31","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1038\/ncb2313","volume":"13","author":"C Kwon","year":"2011","unstructured":"Kwon C, Cheng P, King IN, Andersen P, Shenje L, Nigam V, et al. Notch post-translationally regulates beta-catenin protein in stem and progenitor cells. Nat Cell Biol. 2011;13:1244\u201351.","journal-title":"Nat Cell Biol"},{"key":"1042_CR32","doi-asserted-by":"crossref","unstructured":"Jin YH, Kim H, Ki H, Yang I, Yang N, Lee KY, et al. Beta-catenin modulates the level and transcriptional activity of Notch1\/NICD through its direct interaction. Biochim Biophys Acta. 2009;1793:290\u20139.","DOI":"10.1016\/j.bbamcr.2008.10.002"},{"key":"1042_CR33","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1038\/ng1099","volume":"33","author":"M Nicolas","year":"2003","unstructured":"Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet. 2003;33:416\u201321.","journal-title":"Nat Genet"},{"key":"1042_CR34","doi-asserted-by":"publisher","first-page":"2845","DOI":"10.1182\/blood-2009-07-234377","volume":"115","author":"A Gutierrez","year":"2010","unstructured":"Gutierrez A, Sanda T, Ma W, Zhang J, Grebliunaite R, Dahlberg S, et al. Inactivation of LEF1 in T-cell acute lymphoblastic leukemia. Blood 2010;115:2845\u201351.","journal-title":"Blood"},{"key":"1042_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/srep31894","volume":"6","author":"NC Correia","year":"2016","unstructured":"Correia NC, Fragoso R, Carvalho T, Enguita FJ, Barata JT. MiR-146b negatively regulates migration and delays progression of T-cell acute lymphoblastic leukemia. Sci Rep. 2016;6:31894.","journal-title":"Sci Rep"}],"container-title":["Oncogene"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/s41388-019-1042-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41388-019-1042-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41388-019-1042-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T21:17:55Z","timestamp":1684617475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41388-019-1042-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,4]]},"references-count":35,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,1,30]]}},"alternative-id":["1042"],"URL":"https:\/\/doi.org\/10.1038\/s41388-019-1042-9","relation":{},"ISSN":["0950-9232","1476-5594"],"issn-type":[{"value":"0950-9232","type":"print"},{"value":"1476-5594","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,4]]},"assertion":[{"value":"31 January 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2019","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 September 2019","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 October 2019","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"}}]}}