{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T12:41:46Z","timestamp":1792932106472,"version":"4.5.0"},"reference-count":126,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T00:00:00Z","timestamp":1654732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>The oncometabolite 2-hydroxyglutarate (2-HG) plays a key role in differentiation blockade and metabolic reprogramming of cancer cells. Approximatively 20\u201330% of acute myeloid leukemia (AML) cases carry mutations in the isocitrate dehydrogenase (IDH) enzymes, leading to a reduction in the Krebs cycle intermediate \u03b1-ketoglutarate (\u03b1-KG) to 2-HG. Relapse and chemoresistance of AML blasts following initial good response to standard therapy account for the very poor outcome of this pathology, which represents a great challenge for hematologists. The decrease of 2-HG levels through pharmacological inhibition of mutated IDH enzymes induces the differentiation of AML blasts and sensitizes leukemic cells to several anticancer drugs. In this review, we provide an overview of the main genetic mutations in AML, with a focus on IDH mutants and the role of 2-HG in AML pathogenesis. Moreover, we discuss the impact of high levels of 2-HG on the response of AML cells to antileukemic therapies and recent evidence for highly efficient combinations of mutant IDH inhibitors with other drugs for the management of relapsed\/refractory (R\/R) AML.<\/jats:p>","DOI":"10.3390\/biomedicines10061359","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T10:49:14Z","timestamp":1654771754000},"page":"1359","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["2-Hydroxyglutarate in Acute Myeloid Leukemia: A Journey from Pathogenesis to Therapies"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2807-5461","authenticated-orcid":false,"given":"Vittoria","family":"Raimondi","sequence":"first","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5332-4293","authenticated-orcid":false,"given":"Giulia","family":"Ciotti","sequence":"additional","affiliation":[{"name":"Onco Hematology, Department of Oncology, Veneto Institute of Oncology IOV\u2013IRCCS, 31033 Castelfranco Veneto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Gottardi","sequence":"additional","affiliation":[{"name":"Onco Hematology, Department of Oncology, Veneto Institute of Oncology IOV\u2013IRCCS, 31033 Castelfranco Veneto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7237-6942","authenticated-orcid":false,"given":"Francesco","family":"Ciccarese","sequence":"additional","affiliation":[{"name":"Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV\u2013IRCCS, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,9]]},"reference":[{"key":"ref_1","unstructured":"Boffetta, P., and Hainaut, P. 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