Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Role in Drug Resistance [eRRBS]

ABSTRACT: B cell acute lymphoblastic leukemia (ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of paired diagnosis/relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. Collectively, our data show that the chromatin state at diagnosis varies widely among patients. While the majority of peaks remained stable between diagnosis and relapse, a significant fraction were either lost or newly gained with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome are associated with pathways previously linked to therapy resistance as well as novel candidate pathways through alterations in pyrimidine biosynthesis and downregulation of polycomb repressive complex 2 targets. We also discovered three novel, relapse-specific super-enhancers shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Our results support the role of the epigenome in driving clonal evolution and uncover new candidate pathways associated with relapse.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156532 | GEO | 2020/12/21

REPOSITORIES: GEO