[MLL-rearranged leukemia and menin inhibitors]

Gene rearrangements of the human MLL gene (also known as KMT2A) cause leukemia with poor prognosis by generating MLL fusion oncoproteins. MLL is an epigenetic regulator that has an evolutionarily conserved role maintaining expression of homeotic (HOX) genes during embryonic development. HOX genes and other MLL target genes such as MEIS1 block differentiation and promote proliferation in hematopoietic cells. MLL gene rearrangements generate a constitutively active version of the wild-type protein, which causes overexpression of HOX genes and other target genes, leading to leukemic transformation of normal hematopoietic progenitors. MLL fusion proteins need to form a complex with endogenous menin protein to function as an oncogenic driver. Recently, small compounds that inhibit menin-MLL interaction have been developed and used in clinics in the United States. This review explains how menin inhibitors disrupt MLL fusion protein activity and discusses potential future developments.