Lineage-specific genes are prominent DNA damage hotspots during leukemic transformation of B-cell precursors

Abstract

In human leukemia, lineage - specific genes represent predominant targets of deletion, with lymphoid - specific genes frequently affected in lymphoid leukemia and myeloid - specific genes in myeloid leukemia. T o investigate the basis of lineage - specific alterati ons , we analyzed global DNA damage in primary B - cell precursors expressing leukemia - inducing oncogenes by ChIP - Seq. We identified >1000 sensitive regions, of which B - lineage - specific genes constitute the most prominent targets. Identified hotspots at B - lin eage genes relate to DNA - DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic delet ion in successfully transformed cells. We further show that most identified regions overlap with gene bodies of highly expressed gene s, and that induction of a myeloid lineage phenotype in transformed B - cell precursors promotes de novo DNA damage at myeloid loci. Hence, we demonstrate that lineage - specific transcription predispose s lineage - specific genes in transformed B - cell precursors to DNA damage , which is likely to promote the frequent alteration of lineage - specific genes in human leukemia.