Epigenetic Dependencies in Leukemia
1 PhD project proposal in the IPP summer call 2019
Acute myeloid leukemia (AML) is a disease originating from early hematopoietic progenitors that are characterized by a block of differentiation and clonal expansion. Mutations in the nucleophosmin (NPM1) gene are the most common recurrent mutations in AML and can be found in one third of the cases. Only about one half of the younger patients can be cured by intensive chemotherapy or stem cells transplantation, thereby reflecting the need for novel treatment approaches. While NPM1 mutant leukemias exhibit a distinct gene expression profile including high-level expression of Homeobox (HOX) and MEIS1 transcription factor genes, little is know how these genes are activated and maintained. NPM1 is an intracellular chaperone protein implicated in multiple cellular processes such as proliferation, ribosome, and nucleosome assembly. While mutations in NPM1 cause trapping of the NPM1 protein in the cytoplasm it has remained elusive how these mutations specifically contribute to leukemogenesis. We recently reported that leukemogenic gene expression programs in NPM1 mutant AML are dependent on the menin-MLL1 (KMT2A) chromatin complex. The menin-MLL1 interaction further represents a therapeutic opportunity in these leukemias and can be targeted via novel small molecule inhibitors. How the menin-MLL1 complex may functionally collaborate with mutant NPM1 to cause leukemia is unknown.
PhD project: Deciphering Chromatin-Based Oncogenic Mechanisms in NPM1 mutant Leukemia
The overarching goal of this project is to explore the mechanisms how the mutant NPM1 protein and the menin-MLL1 chromatin complex drive leukemogenesis. We know from previous studies that the mutant NPM1 protein and the menin-MLL1 complex are both required to maintain leukemic gene expression programs in NPM1 mutant AML. In addition, we observed locus specific changes in histone methylation and chromatin state following the inactivation of NPM1 or menin-MLL1. Therefore, we hypothesize that NPM1 and menin-MLL1 control leukemic gene expression via chromatin-based mechanisms. In order to address this question, we will assess human and murine models of NPM1 mutant leukemia for global changes in gene expression following genetic inactivation of NPM1 or menin-MLL1 using CRISPR/Cas9. These results will then be integrated with assessment of histone marks and chromatin state using next generation sequencing techniques. Findings from the genetic inactivation study of menin-MLL1 will be validated using pharmacological inhibition of the menin-MLL1 interaction. The functional effects inactivation of these proteins on cell proliferation, differentiation as well as leukemia initiating capability will be assessed in vitro and in vivo.
Understanding the oncogenic drivers in the most prevalent NPM1 mutant AML subtype will greatly enhance our ability to develop mechanism-based therapeutics for this deadly disease.
This project is most suitable for a PhD student who aims to ask fundamental biological questions about how chromatin-based mechanisms drive oncogenic processes and would like to work on a translational topic that may have the potential to directly affect how patients with leukemia are being treated.
Publications relevant to the project
Kühn MWM, Song E, Feng Z, Sinha A, Chen CW, Desphande AJ, Cusan M, Farnoud NR, Koche RP, Bradner JE, de Stanchina E, McGeehan G, Vassiliou GS, Hoshii T, and Armstrong SA. Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia. Cancer Discovery. 2016;6(10):1166-1181
Kühn MWM*, Hadler MJ*, Daigle SR, Koche RP, Krivtsov AV, Olhava EJ, Caligiuri MA, Huang G, Bradner JE, Pollock RM, Armstrong SA (2015). MLL-PTD leukemia cells are sensitive to small molecule DOT1L inhibition. Haematologica. 2015;100, e190-3. *equal contribution
Krönke J, Bullinger L, Teleanu V, Tschürtz F, Gaidzik VI, Kühn MWM, Rücker FG, Holzmann K, Paschka P, Kapp-Schwörer S, Späth D, Kindler T, Schittenhelm M, Krauter J, Ganser A, Göhring G, Schlegelberger B, Schlenk RF, Döhner H, Döhner K. Clonal evolution in relapsed NPM1 mutated acute myeloid leukemia. Blood. 2013;122(1):100-8.