Targeting Polycomb for treatment of KMT2A-rearranged AML using AML-iPSCs as a model system [RNAseq]

Pediatric and infant Acute myeloid leukemia (AML) often harbor chromosomal translocations involving the KMT2A gene, encoding theKMT2A lysine methyltransferase, and produce in-frame fusions of KMT2A to other chromatin-regulatory proteins. The KMT2A chromosomal rearrangements (KMT2A-r) are associated with bad prognosis, resistance to chemotherapy and high rates of relapse. Therefore, new therapeutic options are needed for this AML subtype. Here, we aim to identify epigenetic regulators involved in the development of KMT2A-r AML that can be exploited towards new treatments. Mutant and isogenic wild type iPSC lines generated from a KMT2A-r patient were differentiated into hematopoietic progenitor cells to investigate differences in gene expression and transcriptional regulation. KMT2A-r cells exhibited an aberrant gene expression signature with delayed or continuously repressed gene expression. The repressed genes display bivalent histone marks and become repressed by the Polycomb repressive complex (PRC). Targeted inhibition of the PRC2 member EZH2 restores the repressed signature to normal expression levels. Our results suggest that inhibition of PRC2 could be complement to treatment of KMT2A-r AML.