Mapping and targeting 3D regulatory elements in leukemia and lymphoma-Supplement

New York University School Of Medicine, New York NY

Investigators

Abstract

Project Summary/Abstract (underlined are the added text and data related to this administrative supplement) Despite cancer being typically depicted as a genetic disease, aberrations in epigenetic regulation and gene expression play a determinant role in transformation and response to therapies. Increased chromatin plasticity gives a survival advantage by expanding epi-clones' repertoire and allowing them to react to 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 designing effective targeted approaches and predicting disease risk. Our team previously investigated changes in large 3D structures using T-cell acute lymphoblastic leukemia (T-ALL) as a model of study. More recently, using H3K27ac HiChIP analysis of enhancer-promoter interactions in T-ALL, we mapped and characterized the biological role of 3D “hubs” as DNA elements that interact with multiple other loci. What we proposed in our recent award application is to expand our analysis and provide a complete characterization of 3D hub interactions in T cell leukemia (T-ALL), the immature early T cell progenitor leukemia (ETP-ALL), and T cell lymphoma, creating a continuum that spans normal T cells, their progenitors and malignant counterparts. By leveraging the mapping of 3D hubs at multiple levels, we expect to better define which are rewired by transformation and contribute to tumor progression or response to drug treatment. In this supplement, we test the hypothesis that cancer health disparities (CHD) are caused -at least in part- by epigenetic changes, and specifically distinct 3D chromosomal organization leading to different expression of genes that control cancer (leukemia) cell self-renewal (stemness), growth and response to drug treatments. We will focus on differences between patients of white (European) and African-American (AA) ancestry, as it is well established that AA patients are at higher risk of certain types of blood cancers, including acute myeloid leukemia (AML). Not only are outcomes worse for Black patients, but also these same patients enroll in clinical trials in lower frequencies and do not have adequately stored blood samples. Our team has recently studied the exomes and transcriptomes of 100 African-American AML patients and found that: a) distinct mutational profiles/frequencies, b) different intrinsic and/or extrinsic dysplasia-causing stressors (like inflammation), c) Black patients with defined mutational profiles had inferior disease free (NPM1, NRAS) and overall (IDH1/2) survival, and, d) transcriptional profiles differed between Black and White patients with NPM1 mutations. What was more important was that the incorporation of ancestry-specific risk markers into current genetic risk stratifications changed risk group assignment for one-third of Black patients and improved their outcome prediction. We thus propose to test the innovative idea that cancer health disparities are not only due to genetic or socio-economic causes, but they are also influenced by epigenetic changes.