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Pathognomonic of APL, PML::RAR\u03b1 fusion protein rewires metabolic pathways to feed anabolic tumor cell\u2019s growth. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO)-based therapies render APL the most curable subtype of AML, yet approximately 1% of cases are resistant and 5% relapse. We characterized the metabolic peculiarity and fuel requirement of PML::RAR\u03b1 expressing cells, to identify new targets for tailored therapies in resistant or relapsed APL patients. We analyzed cell metabolism in primary samples from seven APL patients, comparing them with normal CD34+ cells differentiated to promyelocyte and granulocyte, and different PML::RAR\u03b1 expressing cell lines. We show that the PML::RAR\u03b1 oncoprotein inhibits glycolysis, promotes tricarboxylic acid cycle (TCA), and favors long chain fatty acids (LCFA) catabolism. Targeting CD36 function, that promotes the cellular uptake of fatty acids to feed oxidative phosphorylation (OXPHOS), effectively restores sensitivity to ATO in NB4 ATO-resistant clones. Notably, our data demonstrate that glycolytic impairment via AKT inhibition by PML::RAR\u03b1 renders APL cells reliant on OXPHOS. This dependency confers high sensitivity to the VTX-AZA combination, suggesting the therapeutic efficacy of targeted combination treatment in resistant or relapsed APLs.<\/jats:p>","DOI":"10.1038\/s41375-025-02738-9","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T07:11:45Z","timestamp":1757488305000},"page":"2708-2720","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["PML::RAR\u03b1+ myeloid cells display metabolic alterations that can be targeted to treat resistant\/relapse acute promyelocytic leukemias"],"prefix":"10.1038","volume":"39","author":[{"given":"Alessandra","family":"Zaza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Zardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Banella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Tucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"de Marinis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Gentile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5411-1502","authenticated-orcid":false,"given":"Serena","family":"Travaglini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariadomenica","family":"Divona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1936-3592","authenticated-orcid":false,"given":"Tiziana","family":"Ottone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Germana","family":"Castelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Cerio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela F.","family":"Angelini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0100-6247","authenticated-orcid":false,"given":"Isabella","family":"Faraoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2855-8121","authenticated-orcid":false,"given":"Raffaele","family":"Palmieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paquale","family":"Niscola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Ammatuna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriano","family":"Venditti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Nervi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6164-4761","authenticated-orcid":false,"given":"Maria Teresa","family":"Voso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6763-2876","authenticated-orcid":false,"given":"Gianfranco","family":"Catalano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7682-862X","authenticated-orcid":false,"given":"Nelida Ines","family":"Noguera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"2738_CR1","doi-asserted-by":"crossref","unstructured":"Tallman MS, Altman JK. 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