HMX2 is a transcription factor belonging to the NKL homeobox gene family that functions as a sequence-specific DNA-binding regulator of RNA polymerase II-dependent transcription 1. Its primary role involves specification of intercalated cell subtypes in the kidney collecting duct, where it directs type B intercalated cell differentiation through mutually antagonistic interactions with the transcription factor Dmrt2 23. HMX2 expression is restricted to type B and non-A/non-B intercalated cells, where it activates subtype-specific bicarbonate transporter genes (Slc26a4) essential for systemic acid-base homeostasis 2. Additionally, HMX2 participates in inner ear and hypothalamus development 4. Disease relevance includes acute myeloid leukemia (AML), where aberrant HMX2 expression occurs in ~31% of patients with KMT2A/MLL rearrangements, promoting myeloid differentiation arrest through suppression of differentiation genes and activation of oncogenic pathways 5. HMX2 variants have also been implicated in Ménière's disease, affecting inner ear structural integrity 4. As a transcriptional regulator with significant trans-eQTL effects on multiple genes 1, HMX2 represents a potential therapeutic target for kidney acid-base disorders and hematologic malignancies.