Lineage-Specific Genes Are Prominent DNA Damage Hotspots during Leukemic Transformation of B Cell Precursors

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Bryant Boulianne, Mark E. Robinson, Philippa C. May, Leandro Castellano, Kevin Blighe, Jennifer Thomas, Alistair Reid, Markus Müschen, Jane F. Apperley, Justin Stebbing, Niklas Feldhahn
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 more than 1,000 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. Furthermore, we 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.

Graphical abstract

Teaser

B lineage-specific genes are frequently altered in B lymphoid leukemia. Boulianne et al. show that transformed B cell precursors exhibit transcription-coupled DNA damage at B lineage genes. Likewise, lymphoid-to-myeloid conversion of transformed B cells induces DNA damage at myeloid loci, suggesting that lineage-specific transcription predisposes lineage-specific genes to subsequent alterations as observed in human leukemia.


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