Research progress in Menin-MLL interaction and its inhibitors in MLL-rearranged leukemia

Acute leukemias caused by mixed lineage leukemia (MLL) gene rearrangements (MLL-r) are characterized by high invasiveness and a poor prognosis, with few specific treatment options available. MLL protein is essential in embryonic development and hematopoiesis. It exhibits histone methyltransferase activity and can interact with various proteins through its functional domains, thus regulating downstream target gene expression through epigenetic modifications. MLL-r leads to the formation of MLL fusion proteins (MLL-FPs), in which the C-terminal is replaced by fusion partner proteins; over 100 such partner proteins have been identified to date. In numerous studies of the molecular mechanism, Menin serves as an important cofacter in the leukemogenesis of MLL-FPs and participates in forming the key complex when interacting with the N terminal of MLL protein, resulting in the disregulation of certain targeted genes, which makes the development of Menin-MLL inhibitors theoretically possible. To date, several small molecules have been identified that inhibit Menin-MLL interaction, including thienopyrimidine derivatives, piperidine derivatives, pyrimidine derivatives, and macrocyclic mimic peptides. Based on these prototypes, at least seven drugs are currently undergoing clinical evaluation, with some promising preliminary data regarding safety, tolerability, and efficacy. This review summarizes the structure and function of MLL, the mechanism of the occurrence of MLL-r leukemia, and current Menin-MLL inhibitors tested in MLL-r leukemia.