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Current therapeutic strategies rely on cytoreductive approaches that mitigate disease burden and thromboembolic risk but are not curative. Allogeneic stem cell transplantation remains the only curative option, underscoring the need for novel therapeutic strategies. We previously identified hypoxia\u2013inducible factor 1 (HIF-\u200d\u200d1) as a selective vulnerability in JAK2V617F\u2013positive cells, but the underlying metabolic mechanisms remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In vitro studies utilized 32D cells transduced with an empty vector control,\n                      <jats:italic>Jak2<\/jats:italic>\n                      WT, or\n                      <jats:italic>Jak2<\/jats:italic>\n                      V617F. To evaluate metabolic dependencies, CRISPR-Cas9 was used to generate\n                      <jats:italic>Slc2a1<\/jats:italic>\n                      (GLUT1) and\n                      <jats:italic>Slc2a3<\/jats:italic>\n                      (GLUT3) knockout clones, which were subsequently characterized via RNA sequencing, extracellular flux analysis, and cellular fitness assays (proliferation, viability, and apoptosis). Pharmacological targeted inhibition of GLUT1\/3 was evaluated in human JAK2V617F\u2013mutated post-MPN AML cell lines (SET-2, HEL), primary patient-derived cells and a\n                      <jats:italic>Jak2<\/jats:italic>\n                      V617F knock-in mouse model. Combinatorial efficacy was assessed using the JAK1\/2 inhibitor ruxolitinib.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      JAK2V617F induced HIF-1\u2013dependent metabolic reprogramming, characterized by increased glycolytic flux and oxidative metabolism. Complete abrogation of glucose uptake occurred only upon combined loss of GLUT1 and GLUT3 in\n                      <jats:italic>Jak2<\/jats:italic>\n                      V617F cells, revealing functional redundancy between these transporters that sustains enhanced glycolysis. Disruption of glucose uptake selectively induced stress\u2013associated transcriptional programs and replication stress, triggering an S-phase arrest that culminated in apoptosis and impaired viability, specifically in\n                      <jats:italic>Jak2<\/jats:italic>\n                      V617F cells.\n                    <\/jats:p>\n                    <jats:p>In vivo, pharmacological inhibition of HIF-1 or GLUT induced a reorganization of erythropoiesis to the spleen but did not ameliorate core disease features. In contrast, in vitro GLUT inhibition robustly reduced cell viability in human SET-2 and HEL cell lines and impaired proliferation, viability, and colony formation in patient-derived PBMCs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, these findings establish HIF-1\u2013driven glucose metabolism as a metabolic vulnerability in JAK2V617F-positive MPN. The selective exhaustion of patient\u2013derived clones defines the HIF-1\u2013GLUT1\/3 axis as a central, targetable bottleneck. These data provide a mechanistic rationale for further investigation of HIF-1 or GLUT inhibitors, suggesting that targeting this fundamental requirement may help overcome clinical limitations to achieve disease modification and eradicate the malignant clone.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-026-03018-4","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T05:27:03Z","timestamp":1782192423000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Glucose transport dependency defines a therapeutic vulnerability in JAK2V617F-driven myeloproliferative neoplasms"],"prefix":"10.1186","volume":"24","author":[{"given":"Patrick","family":"Weiand","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Chatain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo A. 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Blood samples from healthy donors were supplied by the Institute for Transfusion Medicine and Cell Therapeutics at RWTH Aachen University Hospital (EK099\/14) after written informed consent.Animal studies were approved by the government authority of Nordrhein-Westfalen, Germany.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Steffen Koschmieder received research funding from Geron, Janssen, AOP Pharma, and Novartis; received consulting fees from Pfizer, Incyte, Ariad, Novartis, AOP Pharma, Bristol Myers Squibb, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Sierra Oncology, PharmaEssentia, Protagonist, Takeda; received payment or honoraria from Novartis, BMS\/Celgene, Pfizer, AstraZeneca, iOMEDICO; received travel\/accommodation support from Alexion, Novartis, Bristol Myers Squibb, Incyte, AOP Pharma, CTI BioPharma, Pfizer, Celgene, Janssen, Geron, Roche, AbbVie, GSK, Sierra Oncology, Kartos, AstraZeneca, Protagonist, and iOMEDICO; had a patent issued for a BET inhibitor at RWTH Aachen University; participated on advisory boards for Pfizer, Incyte, Ariad, Novartis, AOP Pharma, BMS, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Sierra Oncology, PharmaEssentia, Protagonist, Takeda. The other authors declare no conflicts of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"370"}}