[Molecular mechanism and therapeutic targeting of MLL-rearranged leukemia]

Abstract

MLL gene rearrangements cause malignant leukemia, and continue to pose challenges for both patients and their clinicians. Gene rearrangements result in fusion of MLL with more than 80 different partner genes, whose protein products constitutively activate MLL-target genes such as HOXA9 and MEIS1, thereby transforming hematopoietic progenitors into leukemia cells. Interactome analysis identified MENIN as a common associated factor for both MLL fusions and wild-type MLL. Domain mapping analysis of MLL fusion identified the MENIN binding motif and the CXXC domain as the crucial structures for leukemic transformation. The CXXC domain mediates interaction with unmethylated CpGs, which are clustered in the promoter regions. MLL-MENIN interaction leads to further association with LEDGF, which contains a PWWP domain that binds to di/tri-methylated histone H3 K36 (H3K36me2/3). The PWWP and CXXC domains confer stable binding to CpG-rich promoters containing H3K36me2/3 marks so that MLL fusion proteins are able to recognize their target genes. Thus, the protein complex assembly of MENIN, MLL fusion, and LEDGF is the critical event required for leukemia induction, which provides opportunities for drug-mediated inhibition of the MLL fusion protein complex. Small compounds that interfere with MENIN-MLL interaction have been developed by several pharmaceutical companies. Some are now in clinical trials, and one has even obtained FDA approval.

Keywords: Leukemia; MENIN; MLL; Molecularly targeted drug.