{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:53:23Z","timestamp":1790636003242,"version":"4.1.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T00:00:00Z","timestamp":1661990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA162411"],"award-info":[{"award-number":["R01CA162411"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA203584"],"award-info":[{"award-number":["R01CA203584"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"OSUCCC Leukemia Research Program Seed Award","award":["LR182"],"award-info":[{"award-number":["LR182"]}]},{"DOI":"10.13039\/100015979","name":"Pelotonia Fellowship Program Award","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015979","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Cancer Institute CCSG","award":["P30CA016058"],"award-info":[{"award-number":["P30CA016058"]}]},{"name":"OSUCCC Startup Funding"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, but, despite advances in treatment, many patients still experience relapse. CLL cells depend on interactions with supportive cells, and nurse-like cells (NLCs) are the major such cell type. However, little is known about how NLCs develop. Here, we performed DNA methylation analysis of CLL patient\u2013derived NLCs using the 850K Illumina array, comparing CD14+ cells at day 1 (monocytes) versus day 14 (NLCs). We found a strong loss of methylation in AP-1 transcription factor binding sites, which may be driven by MAPK signaling. Testing of individual MAPK pathways (MEK, p38, and JNK) revealed a strong dependence on MEK\/ERK for NLC development, because treatment of patient samples with the MEK inhibitor trametinib dramatically reduced NLC development in vitro. Using the adoptive transfer E\u00b5-TCL1 mouse model of CLL, we found that MEK inhibition slowed CLL progression, leading to lower WBC counts and to significantly longer survival time. There were also lower numbers of mouse macrophages, particularly within the M2-like population. In summary, NLC development depends on MEK signaling, and inhibition of MEK leads to increased survival time in vivo. Hence, targeting the MEK\/ERK pathway may be an effective treatment strategy for CLL.<\/jats:p>","DOI":"10.4049\/jimmunol.2100931","type":"journal-article","created":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T04:51:07Z","timestamp":1672721467000},"page":"1212-1223","source":"Crossref","is-referenced-by-count":10,"title":["Disruption of Nurse-like Cell Differentiation as a Therapeutic Strategy for Chronic Lymphocytic Leukemia"],"prefix":"10.1093","volume":"209","author":[{"given":"Giovanna","family":"Merchand-Reyes","sequence":"first","affiliation":[{"name":"Division of Hematology, The Ohio State University College of Medicine , Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8471-1699","authenticated-orcid":false,"given":"Ramasamy","family":"Santhanam","sequence":"additional","affiliation":[{"name":"Division of Hematology, The Ohio State University College of Medicine , Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5583-9194","authenticated-orcid":false,"given":"Frank H","family":"Robledo-Avila","sequence":"additional","affiliation":[{"name":"Nationwide Children\u2019s Hospital , Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Weigel","sequence":"additional","affiliation":[{"name":"Division of Hematology, The Ohio State University College of Medicine , Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6429-9086","authenticated-orcid":false,"given":"Juan de Dios","family":"Ruiz-Rosado","sequence":"additional","affiliation":[{"name":"Nationwide Children\u2019s Hospital , Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9797-2687","authenticated-orcid":false,"given":"Xiaokui","family":"Mo","sequence":"additional","affiliation":[{"name":"Center for Biostatistics, The Ohio State University College of Medicine , Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Partida-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Nationwide Children\u2019s Hospital , Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A","family":"Woyach","sequence":"additional","affiliation":[{"name":"Division of Hematology, The Ohio State University College of Medicine , Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C","family":"Oakes","sequence":"additional","affiliation":[{"name":"Division of Hematology, The Ohio State University College of Medicine , Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susheela","family":"Tridandapani","sequence":"additional","affiliation":[{"name":"Division of Hematology, The Ohio State University College of Medicine , Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan P","family":"Butchar","sequence":"additional","affiliation":[{"name":"Division of Hematology, The Ohio State University College of Medicine , Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,15]]},"reference":[{"key":"2025021008311136800_r1","article-title":"Key statistics for chronic lymphocytic leukemia","author":"American Cancer Society","year":"2022"},{"key":"2025021008311136800_r2","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/s41571-019-0239-8","article-title":"Chronic lymphocytic leukaemia: from genetics to treatment","volume":"16","author":"Bosch","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"2025021008311136800_r3","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1182\/blood.V96.8.2655","article-title":"Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1","volume":"96","author":"Burger","year":"2000","journal-title":"Blood"},{"key":"2025021008311136800_r4","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/nrc.2016.8","article-title":"The molecular pathogenesis of chronic lymphocytic leukaemia","volume":"16","author":"Fabbri","year":"2016","journal-title":"Nat. Rev. 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