Unraveling MLL1-fusion Leukemia: Epigenetic Revelations from an iPS Cell Point Mutation

Abstract

Much of our understanding of the pathology of acute leukemias is based on studies of 11q23 chromosomal translocations of the gene encoding the mixed lineage leukemia-1 (MLL1) histone H3 lysine 4 (H3K4) methyltransferase. Translocations of the MLL1 gene result in MLL1-fusion (MLL1F) proteins that replace the catalytic SET domain with 1 of more than 80 fusion partners that are thought to drive leukemogenesis through a gain-of-function mechanism. However, this mechanism does not explain how loss of the catalytic SET domain results in upregulated H3K4 trimethylation and target gene expression in MLL1F-leukemic stem cells. In this investigation, we introduced a homozygous loss-of-function point mutation in MLL1 in human induced pluripotent stem cells. The resulting cells mislocalized a different H3K4 trimethyltransferase, SETd1a, to MLL1 target gene promoters and recapitulated a phenotype commonly observed in MLL1F leukemic stem cells, with aberrant histone methylation and gene expression signatures characteristic of "mixed lineage" cells. These results suggest that loss of MLL1 histone methyltransferase activity, and the associated impact on the epigenome, are common molecular features underlying MLL1F pathology.