Stanford Cancer Institute Breakthroughs in Cancer: Ioannis Aifantis, PhD

Title: 3D chromosomal architecture in acute leukemia: impact on disease progression and drug response

Despite cancer being typically depicted as a genetic disease, aberrations in epigenetic regulation and gene expression play a key role in transformation and response to therapies. Derailed from their developmental paths, malignant cells may arrest their differentiation fate and activate alternative programs. Increased chromatin plasticity provides a survival advantage by expanding the repertoire of aberrant “epi-clones” and altering their crosstalk with the immune system, environmental stress or exogenous treatments. Investigating which genetic and epigenetic aberrations alter chromatin homeostasis and how they shape tumor heterogeneity is thus a critical challenge to design effective targeted therapies and predict disease risk. Our laboratory dedicated extensive efforts in trying to understand the non-genetic drivers of leukemia, focusing on epigenetic modifications, long non-coding RNAs and the study of 3D chromatin architecture. We previously investigated changes in large 3D structures in T-cell acute lymphoblastic leukemia (T-ALL), including chromosomal compartments and topological associated domains (TADs). More recently, using H3K27ac HiChIP analysis of enhancer-promoter interactions in T-ALL, we mapped and characterized the biological role of 3D “hubs”, DNA elements that interact with multiple other loci. We hypothesize that hubs represent cell type specific regulatory units responsible for the transcription of key genes, serving as 'headquarters' of cell identity, and might contribute to malignant transformation and shape of therapy response.

#leukemia #CancerResearch

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