Epigenetic control of gene expression in leukemogenesis: Cooperation between wild type MLL and MLL fusion proteins

Abstract

Although there has been great progress in the treatment of human cancers, especially leukemias, many remain resistant to treatment. A major current focus is the development of so-called epigenetic drugs. Epigenetic states are stable enough to persist through multiple cell divisions, but by their very nature are reversible and thus are amenable to therapeutic manipulation. Exciting work in this area has produced a new breed of highly specific small molecules designed to inhibit epigenetic proteins, some of which have entered clinical trials. The current and future development of epigenetic drugs is greatly aided by highly detailed information about normal and aberrant epigenetic changes at the molecular level. In this review we focus on a class of aggressive acute leukemias caused by mutations in the Mixed Lineage Leukemia (MLL) gene. We provide an overview of how detailed molecular analysis of MLL leukemias has provided several early-stage epigenetic drugs and propose that further study of MLL leukemogenesis may continue to provide molecular details that potentially have a wider range of applications in human cancers.

Keywords: MLL; acetylation; chromatin modifications; epigenetic; fusion proteins; histone; leukemia; methylation; small molecule inhibitors; therapy; transcription elongation.

Figure 1.

Structure of the MLL protein. (A) Important protein domains and interactions. MLL possesses 3 AT hooks for binding to AT-rich DNA, a CXXC domain for binding to unmethylated CpG islands, 4 plant homeodomain (PHD) fingers (the third PHD binds to H3K4Me2/3 and CYP33 on the opposite surface), an atypical bromodomain (Bromo), FYRN and FYRC domains, and a C-terminal SET domain that methylates histone H3 on lysine 4. Wild-type MLL is cleaved by Taspase 1 to yield 2 fragments: MLL-N and MLL-C. MLL-N can directly interact with different proteins/complexes, including MENIN, LEDGF, the PAF1 complex (PAF1C), CYP33, PC2, HDAC1, HCF1, and HCF2, and can indirectly bind to BMI-1 and CtBP. The PHD fingers may also interact directly with the ECS^ASB complex. MLL-N is directly phosphorylated by the ATR protein at serine 516. MLL-C can interact with CBP and MOF. The SET domain interacts directly with WDR5 and RBBP5. Interactions with SENP3, DPY30, and AKAP95 are all indirect or partially characterized. (B) Representation of MLL fusion proteins. MLL-FPs retain the N terminus of the wild type protein and lose the C terminus. The breakpoint lies in the region between the CXXC domain and the PHD fingers. (C) Representation of MLL partial tandem duplication. MLL-PTDs duplicate the N terminus of the wild-type protein, which contains the MENIN/LEDGF interaction region, the AT hooks, and the CXXC domain.

Figure 2.

MLL and MLL-FP complexes bound to a gene target. The most common MLL-FPs, such as MLL-AF9, are members of a large super-elongation complex (SEC) that includes the most common MLL fusion partners (AF4, AF9, AF10, ENL), as well as the H3K79 methyltransferase DOT1L, the RNA pol II pause release complex P-TEFb, the elongation factors ELL and EAF, and the PAF1 complex (PAF1C). BRD4 also interacts with this complex. The wild-type MLL complex promotes both H3K4Me and H4K16Ac. The current model proposes that MLL-FPs recruit components of these complexes and then activate RNA polymerase II that is paused at the proximal promoter to promote productive transcription elongation.