Rational p300/CREBBP KAT inhibition in AML

2 PhD projects offered in the IPP winter call 2022

Scientific Background

Acute myeloid leukemias (AML) are aggressive cancers that possess an extraordinary capacity to evolve continuously and adapt under treatment. This characteristic is controlled by adjustments of epigenetic processes and therefore designates drugs targeting epigenetic modifications as suitable therapies in AML. With this project, we intend to support the successful clinical translation of an emerging class of epigenetic modulators – p300/CREBBP lysine acetyltransferase (KAT) inhibitors.

Methodologically, we utilize an integrative approach of state-of-the-art epigenomic, proteomic and functional techniques in multiple orthogonal systems to deconvolute chromatin dynamics and routes of adaptation/resistance that relate to p300/CREBBP KAT inhibition. The necessity of such a complex deconstruction is emphasized through our preliminary results, which show a previously unanticipated repressive function of p300/CREBBP in 50% of all tested AMLs. We also show that the reliance on p300/CREBBP can be enhanced synthetically, for example through chronic inhibition of bromodomain and extraterminal (BET) proteins, and that non-genetic resistance to p300/CREBBP inhibitors causes higher dependency on other druggable epigenetic modulators. Given that the epigenetic adaptation seemingly always unmasks new dependencies, we will exploit the therapeutic potential of a rational sequential epigenetic guidance of AMLs.

PhD Project: Epigenetic adaptation and chromatin dynamics - wet lab

This position will perform epigenomic methods such as PROSeq, ChIPSeq and Cut&Run to follow up on suspected routes of epigenetic adaptation and also to identify newly-induced dependencies. Working models and technical expertise for these or related techniques are established within our laboratory.

If you are interested in this project, please select Sasca (wet) as your group preference in the IPP appcliation platform.

PhD Project: Epigenetic adaptation and chromatin dynamics - bioinformatics

This position will perform computational analysis and integration steps of epigenomic methods, and will construct a prediction model of chromatin dynamics of adaptation and induced vulnerability. Bioinformatic expertise exists within our research group; the candidate will receive all relevant training to successfully complete these tasks.

If you are interested in this project, please select Sasca (bioinf) as your group preference in the IPP appcliation platform.

Publications relevant to this project

Yun H, Narayan N, Vohra S, Mupo A, Giotopoulos G, Madrigal P, Sasca D, Lara-Astasio D, Horton SJ, Agrawal-Singh S, Meduri E, Basheer F, Marando L, Gozdecka M, Dovey OM, Castillo-Venzor A, Wang X, Gallipoli P, Müller-Tidow C, Osborne CS, Vassiliou GS, Huntly BJP. Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction. Nature Genetics 2021 Oct;53(10):1443-1455

Shah V#, Giotopoulos G#, Osaki H#, Meyerhöfer M, Meduri E, Schubert B, Yun H, Horton SJ, Agrawal-Singh S, Haehnel PS, Basheer F, Kühn MWM, Guezguez B, Theobald M, Kindler T, Gallipoli P, Prinjha RK, Huntly BJP*, Sasca D*. Acute resistance to BET inhibitors remodels compensatory remodeling programs via p300 co-activation. Pre-print Biorxiv
*equal contribution and correspondence. Revised manuscript in preparation. Pre-print available on Biorxiv https://doi.org/10.1101/2022.09.14.507850

 

Contact

Dr Daniel Sasca
University Medical Centre Mainz
Department of Hematology, Oncology, and Pneumology
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