Figure 1.

R-2HG promotes leukemogenesis through various mechanisms. Mutated IDH is able to convert the reaction that results in the formation of R-2-HG. Competitive inhibition of multiple classes of α-KG-dependent dioxygenases disrupts DNA methylation and histone methylation resulting in widespread epigenetic abnormalities and a global dysregulation of gene expression. Alternative mechanisms that promote transformation include aberrant HIF-1a signaling and cellular dependency on anti-apoptotic BCL-2. Ivosidenib is a direct inhibitor of mutant thereby preventing the formation of R-2-HG. Venetoclax binds and neutralizes BCL-2.

Abbreviations: α-KG, α-ketoglutarate; R-2-HG, R-2 Hydroxyglutarate; TET, ten-eleven translocation; BCL-2, B-cell lymphoma 2.