{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:12:22Z","timestamp":1790190742214,"version":"4.1.0"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>In relapsed\/refractory acute myeloid leukemia (R\/R-AML), hypoxia-driven chemoresistance is orchestrated by HIF-1\u03b1-induced P-glycoprotein (P-gp) overexpression and subsequent lysosomal sequestration of anthracyclines. Nuclear-cytoplasmic shuttling of the HIF-1\u03b1 prolyl-hydroxylase PHD2 is controlled by chromosome region maintenance 1 (CRM1), which is frequently up-regulated in AML; however, whether pharmacologic CRM1 inhibition restores PHD2 nuclear availability to accelerate HIF-1\u03b1 degradation and reverse chemoresistance remains undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      AML cell lines (MV4\u201311 and MOLM13) were cultured under normoxic or hypoxic conditions. The effects of hypoxia on drug sensitivity, intracellular drug distribution, and protein expression were assessed using CCK-8 assays, immunofluorescence, Western blot, and flow cytometry. Genetic and pharmacological inhibition of P-gp, HIF-1\u03b1, and CRM1 was performed to validate their roles in chemoresistance. Hypoxia-adapted zebrafish CHT xenografts were employed for\n                      <jats:italic>in vivo<\/jats:italic>\n                      validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Hypoxia reduced AML cell sensitivity to DNR, increased HIF-1\u03b1 and P-gp expression, and promoted lysosomal sequestration of DNR. Inhibition of P-gp or HIF-1\u03b1 reversed these effects. CRM1 and PHD2 expression increased under hypoxia, but nuclear accumulation of PHD2 decreased. Selinexor restored PHD2 nuclear localization, promoted HIF-1\u03b1 degradation, reduced P-gp expression, and enhanced DNR nuclear accumulation. Combination treatment with Selinexor and DNR significantly increased apoptosis and DNA damage\n                      <jats:italic>in vitro<\/jats:italic>\n                      and reduced leukemia burden in zebrafish xenografts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      CRM1 inhibition by Selinexor re-establishes nuclear PHD2 residency, increases the degradation of HIF-1\u03b1 in hypoxia, abrogates P-gp-mediated lysosomal anthracycline trapping, and confers potent\n                      <jats:italic>in-vitro<\/jats:italic>\n                      and\n                      <jats:italic>in-vivo<\/jats:italic>\n                      chemosensitization. These data provide mechanistic rationale for integrating Selinexor into salvage regimens for R\/R-AML.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1710230","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T06:31:53Z","timestamp":1764225113000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibition of CRM1 reverses hypoxia-driven chemoresistance in acute myeloid leukemia via overcoming HIF-1\u03b1-mediated lysosomal sequestration"],"prefix":"10.3389","volume":"16","author":[{"given":"Xiaohui","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuntian","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hancheng","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxin","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"B1","article-title":"Outcomes of patients with relapsed or refractory acute myeloid leukemia: a population-based real-world study","volume":"10","author":"Brandwein","year":"2020","journal-title":"Am J Blood Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019001982","article-title":"How I treat relapsed or refractory AML","volume":"136","author":"DeWolf","year":"2020","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.22","article-title":"Impact of pretreatment characteristics and salvage strategy on outcome in patients with relapsed acute myeloid leukemia","volume":"31","author":"Schlenk","year":"2017","journal-title":"Leukemia"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-0245-2","article-title":"Bone marrow niches in haematological Malignancies","volume":"20","author":"Mendez-Ferrer","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020002832","article-title":"Hypoxia favors chemoresistance in T-ALL through an HIF1alpha-mediated mTORC1 inhibition loop","volume":"5","author":"Fahy","year":"2021","journal-title":"Blood Adv"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4155\/fmc-2019-0350","article-title":"The growing evidence for targeting P-glycoprotein in lysosomes to overcome resistance","volume":"12","author":"Stefan","year":"2020","journal-title":"Future Med Chem"},{"key":"B7","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1186\/s13045-021-01199-8","article-title":"A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia","volume":"14","author":"Zeng","year":"2021","journal-title":"J Hematol Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.11246","article-title":"HIF-1alpha forms regulatory loop with YAP to coordinate hypoxia-induced adriamycin resistance in acute myeloid leukemia cells","volume":"44","author":"Zhu","year":"2020","journal-title":"Cell Biol Int"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406026200","article-title":"Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor","volume":"279","author":"Appelhoff","year":"2004","journal-title":"J Biol Chem"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M804390200","article-title":"Nuclear oxygen sensing: induction of endogenous prolyl-hydroxylase 2 activity by hypoxia and nitric oxide","volume":"283","author":"Berchner-Pfannschmidt","year":"2008","journal-title":"J Biol Chem"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg392","article-title":"HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia","volume":"22","author":"Berra","year":"2003","journal-title":"EMBO J"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.109041","article-title":"Oxygen sensing by the prolyl-4-hydroxylase PHD2 within the nuclear compartment and the influence of compartmentalisation on HIF-1 signalling","volume":"125","author":"Pientka","year":"2012","journal-title":"J Cell Sci"},{"key":"B13","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1038\/s41571-020-00454-0","article-title":"Author Correction: The nuclear export protein XPO1 - 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