Mixed-Lineage Leukemia Fusions and Chromatin in Leukemia

Abstract

Recent studies have shown the importance of chromatin-modifying complexes in the maintenance of developmental gene expression and human disease. The mixed lineage leukemia gene (MLL1) encodes a chromatin-modifying protein and was discovered as a result of the cloning of translocations involved in human leukemias. MLL1 is a histone lysine 4 (H3K4) methyltransferase that supports transcription of genes that are important for normal development including homeotic (Hox) genes. MLL1 rearrangements result in expression of fusion proteins without H3K4 methylation activity but may gain the ability to recruit other chromatin-associated complexes such as the H3K79 methyltransferase DOT1L and the super elongation complex. Therefore, chromosomal translocations involving MLL1 appear to directly perturb the regulation of multiple chromatin-associated complexes to allow inappropriate expression of developmentally regulated genes and thus drive leukemia development.

Figure 1.

Schematic drawing of KMT2A, MLL fusions, and MLL-PTD with indicated domains. KMT2A, Lysine methyltransferase 2A; MLL, mixed-lineage leukemia; PTD, partial tandem duplication; NLS, nuclear localization signal; FYRN, FY-rich amino terminal; TAS, transcription activation domain; FYRC, FY-rich carboxyl terminal; SET, Su(Var)39, enhancer of zeste, and trithorax; AF4(9)(10), ALL1-Fused gene from chromosome 4(9)(10) protein; ENL, eleven nineteen leukemia.

Figure 2.

Schematic representation of domain composition of the KMT2 (lysine methyltransferase 2) family of proteins.