{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T20:22:41Z","timestamp":1775938961038,"version":"3.50.1"},"reference-count":19,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T00:00:00Z","timestamp":1653004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100002275","name":"Pediatric Cancer Foundation","doi-asserted-by":"publisher","award":["Fellowship Training Grant"],"award-info":[{"award-number":["Fellowship Training Grant"]}],"id":[{"id":"10.13039\/100002275","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>RAS<\/jats:italic> mutations are frequently observed in childhood B\u2010cell acute lymphoblastic leukemia (B\u2010ALL) and previous studies have yielded conflicting results as to whether they are associated with a poor outcome. We and others have demonstrated that the mitogen\u2010activated protein kinase\u2013extracellular signal\u2010regulated kinase (MAPK) pathway can be activated through epigenetic mechanisms in the absence of <jats:italic>RAS<\/jats:italic> pathway mutations. Herein, we examined whether MAPK activation, as determined by measuring phosphorylated extracellular signal\u2010regulated kinase (pERK) levels in 80 diagnostic patient samples using phosphoflow cytometry, could be used as a prognostic biomarker for pediatric B\u2010ALL. The mean fluorescence intensity of pERK (MFI) was measured at baseline and after exogenous stimulation with or without pretreatment with the mitogen\u2010activated protein kinase kinase (MEK) inhibitor trametinib. Activation levels (MFI stimulated\/MFI baseline) ranged from 0.76 to 4.40 (median\u00a0=\u00a01.26), and inhibition indexes (MFI stimulated\/MFI trametinib stimulated) ranged from 0.439 to 5.640 (median\u00a0=\u00a01.30), with no significant difference between patients with wildtype versus mutant <jats:italic>RAS<\/jats:italic> for either. Logistic regression demonstrated that neither MAPK activation levels nor <jats:italic>RAS<\/jats:italic> mutation status at diagnosis alone or in combination was prognostic of outcome. However, 35% of <jats:italic>RAS<\/jats:italic> wildtype samples showed MAPK inhibition indexes greater than the median, thus raising the possibility that therapeutic strategies to inhibit MAPK activation may not be restricted to patients whose blasts display Ras pathway defects.<\/jats:p>","DOI":"10.1002\/pbc.29771","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T12:54:12Z","timestamp":1653051252000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Activation of the mitogen\u2010activated protein kinase\u2013extracellular signal\u2010regulated kinase pathway in childhood B\u2010cell acute lymphoblastic leukemia"],"prefix":"10.1002","volume":"69","author":[{"given":"Pallavi M.","family":"Pillai","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Hematology\u2010Oncology, Mount Sinai Kravis Children's Hospital Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Mallory","sequence":"additional","affiliation":[{"name":"Rutgers Cancer Institute of New Jersey Robert Wood Johnson Medical School  New Brunswick New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna","family":"Pierro","sequence":"additional","affiliation":[{"name":"Northwell Health Staten Island University Hospital  Staten Island New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Saliba","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center NYU Langone Health  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Newman","sequence":"additional","affiliation":[{"name":"Penn Medicine University of Pennsylvania Health System  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiyuan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Population Health, Division of Biostatistics NYU Grossman School of Medicine  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teena","family":"Bhatla","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children's Hospital of New Jersey at NBI RWJBarnabas Health  Newark New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Raetz","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center NYU Langone Health  New York New York USA"},{"name":"Department of Pediatrics, Division of Pediatric Hematology\/Oncology NYU Grossman School of Medicine  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William L.","family":"Carroll","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center NYU Langone Health  New York New York USA"},{"name":"Department of Pediatrics, Division of Pediatric Hematology\/Oncology NYU Grossman School of Medicine  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8090-0986","authenticated-orcid":false,"given":"Nikki A.","family":"Evensen","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center NYU Langone Health  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.10.7508"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI12807"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403859"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2402460"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-05-021071"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-04-639138"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-04-531871"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.303"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403272"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7604"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1608420113"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-1145"},{"issue":"3","key":"e_1_2_9_14_1","first-page":"1997","article-title":"ERK\/MAPK 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