2-Hydroxyglutarate in Acute Myeloid Leukemia: A Journey from Pathogenesis to Therapies

Abstract

The oncometabolite 2-hydroxyglutarate (2-HG) plays a key role in differentiation blockade and metabolic reprogramming of cancer cells. Approximatively 20–30% of acute myeloid leukemia (AML) cases carry mutations in the isocitrate dehydrogenase (IDH) enzymes, leading to a reduction in the Krebs cycle intermediate α-ketoglutarate (α-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.

Separation of GVL from GVHD -location, location, location

“…This localized T-cell suppression can be promptly reversed by IDH-inhibition. Although the role of IDH1 mutation on TIME is less clear in AML ( 116 ), these results suggest that IDH inhibitors may induce localized GVL effects around AML cells without affecting systemic GVHD.…”

Synergetic Multichiral Covalent Organic Framework for Enantioselective Recognition and Separation

“…The relative intensities of ibuprofen enantiomers are significantly different at 1180, 1357, 1550, and 1639 cm –1 (Figure a). 2-HG and LDH are potential biomarkers of acute leukemia. , The clinical study found that high concentrations of D -2-HG have been identified in cancer cells, including gliomas, glioblastomas, and acute myelogenous leukemia. − The Raman peak shifts and relative intensity of LDH at 950, 1312, 1365, and 1453 cm –1 are significantly different. As shown in Figure a, the Raman spectrum of 2-HG exhibits feature bands at 1050, 1320, and 1615 cm –1 .…”

Plant-derived extracts and metabolic modulation in leukemia: a promising approach to overcome treatment resistance

“…In AML, IDH mutations lead to the consumption of NADPH by converting isocitrate to 2-HG, considered an oncometabolite. The accumulation of 2-HG triggers the inhibition of α-KG-dependent enzymes, such as TET2 (Tet methylcytosine dioxygenase 2) demethylase, and consequently alters gene expression by favoring DNA hypermethylation (Raimondi et al, 2022). The improvement in mitochondrial oxidative metabolism has been associated with resistance to the use of IDH inhibitors and the concomitant use of OxPhos inhibitors improves the efficacy of treatment against IDH mutated in vivo in AML (Stuani et al, 2021).…”