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In the present study, we demonstrate that leukemic cells residing in the liver display unique biological properties and also contribute to systemic changes that influence physiologic responses to chemotherapy. Specifically, the liver microenvironment induces metabolic adaptations via upregulating expression of endothelial lipase in leukemia cells, which not only stimulates tumor cell proliferation through polyunsaturated fatty acid\u2013mediated pathways, but also promotes survival by stabilizing antiapoptotic proteins. Additionally, hepatic infiltration and tissue damage caused by malignant cells induces release of liver-derived enzymes capable of degrading chemotherapy drugs, an event that further protects leukemia cells from conventional therapies. Together, these studies demonstrate a unique role for liver in modulating the pathogenesis of leukemic disease and suggest that the hepatic microenvironment may protect leukemia cells from chemotherapeutic challenge.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>The studies presented herein demonstrate that the liver provides a microenvironment in which leukemia cells acquire unique metabolic properties. The adaptations that occur in the liver confer increased resistance to chemotherapy. Therefore, we propose that therapies designed to overcome liver-specific metabolic changes will yield improved outcomes for patients with leukemia.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 211<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-20-0318","type":"journal-article","created":{"date-parts":[[2020,10,7]],"date-time":"2020-10-07T14:10:10Z","timestamp":1602079810000},"page":"500-519","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG"],"prefix":"10.1158","volume":"11","author":[{"given":"Haobin","family":"Ye","sequence":"first","affiliation":[{"name":"1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Minhajuddin","sequence":"additional","affiliation":[{"name":"1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Krug","sequence":"additional","affiliation":[{"name":"1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Pei","sequence":"additional","affiliation":[{"name":"1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Hsing","family":"Chou","sequence":"additional","affiliation":[{"name":"2Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, Ohio."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Culp-Hill","sequence":"additional","affiliation":[{"name":"3Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Ponder","sequence":"additional","affiliation":[{"name":"1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"De Bloois","sequence":"additional","affiliation":[{"name":"4Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Schniedewind","sequence":"additional","affiliation":[{"name":"4Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L.","family":"Amaya","sequence":"additional","affiliation":[{"name":"1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anagha","family":"Inguva","sequence":"additional","affiliation":[{"name":"1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett M.","family":"Stevens","sequence":"additional","affiliation":[{"name":"1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6519-4860","authenticated-orcid":false,"given":"Daniel A.","family":"Pollyea","sequence":"additional","affiliation":[{"name":"1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Christians","sequence":"additional","affiliation":[{"name":"4Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8162-6758","authenticated-orcid":false,"given":"H. Leighton","family":"Grimes","sequence":"additional","affiliation":[{"name":"2Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, Ohio."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2258-6490","authenticated-orcid":false,"given":"Angelo","family":"D'Alessandro","sequence":"additional","affiliation":[{"name":"1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado."},{"name":"3Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0869-3465","authenticated-orcid":false,"given":"Craig T.","family":"Jordan","sequence":"additional","affiliation":[{"name":"1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, 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