Characterization of chromatin changes induced by Menin-MLL inhibition in NPM1c mutant acute myeloid leukemia
Final Report Abstract
Nucleophosmin (NPM1) mutations are among the most common aberrations in acute myeloid leukemia (AML) and cause a characteristic stem cell-like gene expression pattern including the upregulation of HOXA/B cluster genes and their co-factors MEIS1. Despite its high prevalence, the molecular mechanisms of leukemogenesis remains poorly understood and targeted therapy options are lacking. In this study we used Npm1c knock-in to shown that expression of Npm1c can induce self-renewal in myeloid progenitor cells and give rise to preleukemic clones that progress to AML. We thereby establish the myeloid progenitor compartment as potential cell of origins in NPM1c mutant leukemia. We then used the Npm1c knock-in mouse model to demonstrate that Menin-MLL interaction inhibition (Menin-i) is highly effective in eradicating Npm1c mutant pre-leukemic engraftment. Menin-MLL inhibition was also highly effective in fully developed AML which we showed using several patient derived xenograft models of NPM1c, NPM1c/DNMT3a mutant and very aggressive NPM1c/FLT3ITD mutant leukemias. Our studies have shown that NPM1c mutant leukemias depend on the histone methyltransferase MLL and its adaptor protein Menin to maintain leukemia gene expression and proliferation. The interaction between Menin and MLL is essential for the recruitment of the MLL complex to a subgroup of its target genes, such as MEIS1, which are in turn essential for maintaining leukemic self-renewal. Therapeutic targeting of the Menin-MLL interaction with small molecule inhibitors causes a loss of self-renewal and subsequent differentiation of NPM1c leukemia cells. These findings were published in "Science" in 2020. The striking sensitivity we observed in NPM1c patient derived xenograft models resulted in the inclusion of NPM1c mutant patients in a phase I/II clinical trial using the clinical compound derived from VTP-50469 called SNDX-5613 (NCT04065399). Overall, these studies improved our understanding of NPM1c mutant leukemia development and how to reverse the stem cell signature driven by NPM1c. Further studies are necessary to understand the link between NPM1c and the chromatin modifier MLL.
Publications
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Location, Location, Location: Mutant NPM1c Cytoplasmic Localization Is Required to Maintain Stem Cell Genes in AML. Cancer Cell. Sep 2018
Uckelmann HJ, Armstrong SA, Stone RM
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A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia. Cancer Cell. Dec 2019
Krivtsov AV, Evans K, Gadrey JY, Eschle BK, Hatton C, Uckelmann HJ, Ross KN, Perner F, Olsen SN, Pritchard T, McDermott L, Jones CD, Jing D, Braytee A, Chacon D, Earley E, McKeever BM, Claremon D, Gifford AJ, Lee HJ, Teicher BA, Pimanda JE, Beck D, Perry JA, Smith MA, McGeehan GM, Lock RB, Armstrong SA
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Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. Science. Jan 2020
Uckelmann HJ, Kim SM, Wong EM, Hatton C, Giovinazzo H, Gadrey JY, Krivtsov AV, Rücker FG, Döhner K, McGeehan GM, Levine RL, Bullinger L, Vassiliou GS, Armstrong SA
