[Targeting leukemia-specific transcriptional hubs in AML: menin inhibition and beyond]

The therapeutic landscape for acute myeloid leukemia (AML) has undergone a paradigm shift with the introduction of BCL-2 inhibitors. Despite these advances, the treatment of refractory and relapsed cases remains a challenge. Recent molecular insights have revealed that diverse genetic aberrations-including KMT2A rearrangements, NPM1 mutations, and NUP98 fusions-converge on a common oncogenic transcriptional program characterized by the overexpression of HOXA/B clusters and MEIS1. These HOX-dysregulated leukemias are considered to represent a molecular subtype dependent on maintenance of the HOX transcriptional program mediated by the KMT2A-menin complex. Based on this biological framework, menin inhibitors have demonstrated high efficacy in AML with KMT2A rearrangements and NPM1 mutations. More recently, accumulating evidence suggests that liquid-liquid phase separation-mediated transcriptional hub formation contributes to this potent transcriptional circuitry. Of particular translational relevance, emerging evidence identifies the nuclear export protein XPO1 (exportin-1) as a critical structural scaffold required for the assembly and maintenance of these transcriptional condensates, suggesting that XPO1 inhibition may represent a mechanistically distinct therapeutic strategy to dismantle the HOX transcriptional network. In this review, we summarize the molecular basis of HOX-driven leukemias and discuss the latest clinical developments in targeted therapies, with a particular focus on menin and XPO1 inhibition.