Daniel Savic Lab

To conduct our study of genomic alterations that lead to drug resistance, we explore both the genetic and epigenetic roots of these alterations. In our study of genetic-based alterations, our laboratory utilizes genome-wide association studies (GWAS) to examine DNA sequence alterations at cis-regulatory elements, which function as key regulators of gene expression. Our GWA studies examine inherited genetic variants that associate with relapse in ALL or with sensitivity to chemotherapeutic agents. To examine epigenetic-based gene alterations, we examine differences in open chromatin accessibility at cis-regulatory elements. This approach allows us to use chromatin accessibility as a proxy for the activity of these elements so we may better understand how changes in their activity impact resistance to pharmaceuticals. We currently have open chromatin maps in over 200 primary ALL samples from patients, and through our annotation of these samples, we can develop a deeper understanding of the ALL epigenome. A next step for our lab is to move beyond simple annotation and develop functional assays, such as massively parallel reporter assays (MPRAs), that play an important role in uncovering active cis-regulatory elements within the genome.

An exciting area of study outside leukemia-related research focuses on the genetic mechanisms that contribute to glucocorticoid (i.e. steroid) resistance. To address this, we work to understand how genetic and epigenetic alterations to glucocorticoid response elements lead to differences in sensitivity to steroids. On a basic-science level, we seek to answer how GR, the nuclear receptor transcription factor activated by glucocorticoids, functions to regulate gene expression. By understanding how GR functions, we can better understand what impact genomic alterations might have on GR transcriptional regulation and steroid resistance. We are currently mapping these genomic changes and identifying the regulatory mechanisms that impact glucocorticoid response element function and steroid resistance.

To conduct our research, our laboratory utilizes cutting-edge technology and approaches to examine the basis of drug resistance in pediatric patients. Much of our work includes functional genomics, analyzed through next-generation sequencing approaches such as ChIP-seq, ATAC-seq, and RNA-seq. We also partner with St. Jude’s Center for Advanced Genome Engineering (CAGE) to conduct noncoding genome editing with the CRISPR-Cas9 system. Our collaboration with these shared resources, as well as other laboratories and departments, enables us to conduct research that expands our current understanding of the relationship between gene regulation and drug resistance.