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

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posted on 2023-06-09, 13:46 authored by Bryant Boulianne, Mark E Robinson, Philippa C May, Leandro CastellanoLeandro 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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Cell Reports

ISSN

2211-1247

Publisher

Elsevier

Issue

7

Volume

18

Page range

1687-1698

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-06-15

First Open Access (FOA) Date

2018-06-15

First Compliant Deposit (FCD) Date

2018-06-15

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