Daniel Savic Lab

To define the regulatory architecture governing therapeutic response in childhood leukemia, our laboratory applies functional genomic methods to identify active cis-regulatory elements and their target interactions in leukemia cells. These studies established one of the largest chromatin accessibility resources in acute lymphoblastic leukemia to date, profiling primary leukemia cells from more than 150 patients across molecular subtypes. These studies provide a framework for understanding how enhancer networks and regulatory states govern leukemia biology and therapeutic response.

Therapeutic agents induce widespread remodeling of enhancer networks and chromatin state. Our laboratory investigates how therapeutic agents reshape transcription factor occupancy, enhancer activity, and cellular regulatory programs to influence therapeutic response and resistance in childhood leukemia. Using integrated epigenomic and transcriptomic profiling approaches, we map dynamic transcriptional and chromatin responses to commonly used antileukemic agents. By integrating these drug-induced regulatory responses with chromatin profiling from drug-sensitive and drug-resistant primary patient samples, we identify pre-existing regulatory states associated with therapeutic resistance. These studies define how therapeutic agents remodel enhancer networks and how pre-existing regulatory states influences therapeutic response and drug resistance.

Many disease-associated genetic variants occur within noncoding regulatory DNA. Our laboratory investigates how inherited and somatic noncoding variants alter enhancer activity, transcription factor binding, and therapeutic response in childhood leukemia. To experimentally characterize these regulatory mechanisms at scale, we employ massively parallel reporter assays to measure the effects of thousands of regulatory variants on enhancer function and gene expression. Complementary CRISPR-based functional screening approaches identify enhancer perturbations that influence therapeutic response and drug resistance phenotypes. By integrating these approaches with patient-derived genomic datasets, we define how noncoding variation and enhancer dysfunction contribute to therapeutic response and drug resistance.

Collectively, these studies aim to define the regulatory mechanisms governing therapy response and drug resistance in childhood leukemia. By identifying how drugs remodel enhancer networks and regulatory states, our work seeks to advance precision medicine approaches for pediatric leukemia and uncover new therapeutic strategies capable of overcoming drug resistance. More broadly, these studies establish general principles for how regulatory states influence therapeutic response across cancer and other disease settings.