{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T19:44:01Z","timestamp":1774122241778,"version":"3.50.1"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2007,10,4]],"date-time":"2007-10-04T00:00:00Z","timestamp":1191456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["European J of Haematology"],"published-print":{"date-parts":[[2008,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The reduced folate carrier (RFC) is a transmembrane protein that mediates cellular uptake of reduced folates and antifolate drugs, including methotrexate (MTX). Acquired alterations of the <jats:italic>RFC<\/jats:italic> gene have been associated with resistance to MTX in cancer cell lines and primary osteosarcomas. Here, we examined <jats:italic>RFC<\/jats:italic> for mutations and promoter hypermethylation in (i) the inherently MTX\u2010resistant lymphoma cell line (RL); (ii) 30 paired cases of acute lymphoblastic leukemia (ALL) obtained at diagnosis and at relapse after treatment with MTX; and (iii) 25 cases of diffuse large B\u2010cell lymphoma (DLBCL) at diagnosis, none of which had been previously exposed to MTX. Aberrant hypermethylation of the <jats:italic>RFC<\/jats:italic> promoter occurred in RL cells and two of the primary DLBCLs. In one additional DLBCL, a single\u2010base substitution in <jats:italic>RFC<\/jats:italic> was identified, leading to the introduction of a premature termination codon (c.1396C&gt;T; p.Q466X). A missense mutation affecting the 11th transmembrane domain of RFC (c.1250T&gt;C; p.I417T) was found in one case of ALL at diagnosis. In ALL, <jats:italic>RFC<\/jats:italic> promoter hypermethylation was found neither at diagnosis nor at relapse and thus is not a common cause of low levels of RFC expression associated with adverse outcome. In DLBCL, genetic and epigenetic alterations of <jats:italic>RFC<\/jats:italic> were detected at diagnosis in the absence of a selective MTX pressure, suggesting that these alterations may possibly contribute to the development of lymphoma.<\/jats:p>","DOI":"10.1111\/j.1600-0609.2007.00980.x","type":"journal-article","created":{"date-parts":[[2007,10,4]],"date-time":"2007-10-04T23:08:22Z","timestamp":1191539302000},"page":"61-66","source":"Crossref","is-referenced-by-count":14,"title":["Genetic and epigenetic alterations of the reduced folate carrier in untreated diffuse large B\u2010cell lymphoma"],"prefix":"10.1111","volume":"80","author":[{"given":"Ingelise Bjerring","family":"Kastrup","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesper","family":"Worm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Ralfkiaer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Hokland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Per","family":"Guldberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirsten","family":"Gr\u00f8nb\u00e6k","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2007,12,13]]},"reference":[{"key":"e_1_2_5_2_2","first-page":"113","volume-title":"Homocysteine in Health and Disease","author":"Cook R","year":"2001"},{"key":"e_1_2_5_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.19.1.91"},{"key":"e_1_2_5_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206946"},{"key":"e_1_2_5_5_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.3.1013"},{"key":"e_1_2_5_6_2","first-page":"837","article-title":"Sequence alterations in the reduced folate carrier are observed in osteosarcoma tumor samples","volume":"9","author":"Yang R","year":"2003","journal-title":"Clin Cancer Res"},{"key":"e_1_2_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2004.05.008"},{"key":"e_1_2_5_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M103181200"},{"key":"e_1_2_5_9_2","doi-asserted-by":"publisher","DOI":"10.1080\/1042819031000077124"},{"key":"e_1_2_5_10_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.10.3205"},{"key":"e_1_2_5_11_2","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-05-0515"},{"key":"e_1_2_5_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-02-0557"},{"key":"e_1_2_5_13_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.10587"},{"key":"e_1_2_5_14_2","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1182\/blood-2006-07-034330","article-title":"Gene\u2013nutrient interactions among determinants of folate and one\u2010carbon metabolism on the risk of non\u2010Hodgkin lymphoma: NCI\u2010SEER case\u2010control study","volume":"109","author":"Lim U","year":"2007","journal-title":"Blood"},{"key":"e_1_2_5_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/82.6.501"},{"key":"e_1_2_5_16_2","unstructured":"World Health Organisation Classification of Tumours.Pathology and genetics of tumours of haematopoietic and lymphoid tissues. 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