Characterization of chromatin changes induced by Menin-MLL inhibition in NPM1c mutant acute myeloid leukemia

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NPM1c is the most common type of cytogenetically normal AML. Despite the high prevalence, the molecular mechanisms of leukemogenesis remain poorly understood and targeted therapy options are lacking. Recent data from our group has shown that NPM1c can induce self-renewal in myeloid progenitor cells and give rise to preleukemic clones that develop late onset AML in mouse models. We used this mouse model to demonstrate that Menin-MLL inhibition is highly effective in eradicating NPM1c mutant pre-leukemic engraftment as well as fully developed AML in PDX models. Our data suggest that Menin and its interaction with MLL are essential for maintaining leukemic self-renewal of NPM1c mutant cells. Gene expression analysis revealed that Menin inhibition leads to a rapid loss of expression of HOX Co-factors MEIS1 and PBX3. Unexpectedly, we did not observe any loss of HOXA/B expression which was reported by other groups using older Menin inhibitor molecules in the context of MLL-rearranged leukemias. To understand the difference in the epigenetic landscape we want to thoroughly analysis chromatin changes induced by Menin-MLL inhibition. First and foremost we will study the chromatin occupancy changes in Menin and MLL after disrupting their interaction. NPM1c mutant cells were also shown to be responsive to histone methyltransferase DOT1L inhibitors. Therefore, we will investigate the behavior of DOT1l and the activating histone marks deposited MLL and DOT1L (H3K4 and H3K79) in order to investigate whether these factors are changing their distribution upon Menin inhibition. These changes in the chromatin landscape will be analyzed for their correlation with changes in gene expression obtained by RNAseq. With the proposed experiments, we will gain deeper insight into the chromatin dynamics in NPM1c AML after disruption of the Menin-MLL.