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In the current study, the effect of iron in response to methotrexate and its underlying mechanisms were investigated in pALL cells. CCRF\u2010CEM and Nalm6 cell lines were selected as T and B\u2010ALL subtypes. Cells were pretreated with ferric ammonium citrate, exposed to the IC50 concentration of MTX and cell viability was assessed using MTT, colony formation, and flow cytometry assays. Iron\u2010loaded cells were strongly resistant to MTX cytotoxicity. The inhibitory effect of N\u2010acetyl cysteine to reverse the acquired MTX resistance was greater than that of the iron chelator, deferasirox, highlighting the importance of iron\u2010mediated ROS in MTX resistance. Subsequently, the upregulation of <jats:italic>BCL2<\/jats:italic>, <jats:italic>SOD2<\/jats:italic>, <jats:italic>NRF2<\/jats:italic>, and <jats:italic>MRP1<\/jats:italic> was confirmed using quantitative RT\u2010PCR. Moreover, a positive correlation was demonstrated between the <jats:italic>MRP1<\/jats:italic> expression levels and bone marrow iron storage in pALL patients. Further supporting our findings were the hematoxylin and eosin\u2010stained histological sections showing that iron\u2010treated nude mice xenografts demonstrated significantly more liver damage than those unexposed to iron. Overall, iron is introduced as a player with a novel role contributing to methotrexate resistance in pALL. Our findings suggest that the patients' bone marrow iron stores are necessary to be assessed during the chemotherapy, and transfusions should be carefully administrated.<\/jats:p>","DOI":"10.1002\/cam4.2982","type":"journal-article","created":{"date-parts":[[2020,3,16]],"date-time":"2020-03-16T14:05:14Z","timestamp":1584367514000},"page":"3537-3550","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Iron protects childhood acute lymphoblastic leukemia cells from methotrexate cytotoxicity"],"prefix":"10.1002","volume":"9","author":[{"given":"Marjan","family":"Abedi","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular biology &amp; Microbiology, Faculty of Biological Science and Technology University of Isfahan Isfahan 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