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

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. To investigate the basis of lineage-specific alterations, 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-lineage genes relate to DNA-DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic deletion in successfully transformed cells. We further show that most identified regions overlap with gene bodies of highly expressed genes, 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 predisposes 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. Overall design: ChIP-seq of serine 139-phosphorylated H2AX (gH2AX) and lysine 27 acetylated H3 (H3K27ac) under BCR-ABL1, C-MYC, and BCR-ABL1 +/-CEBPA (DOX) expressing conditions with input, isotype and empty vector controls. BCR-ABL1 and C-MYC gH2AX ChIPseq data are repeated in duplicate, all others are single replicates. RNA-seq was additionally performed on BCR-ABL1, C-MYC and EV expressing cells in duplicate.