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

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Title: Lineage-specific genes are prominent DNA damage hotspots during leukemic transformation of B-cell precursors
Authors: Boulianne, B
Robinson, ME
May, PC
Castellano, L
Blighe, K
Thomas, J
Reid, A
Muschen, M
Apperley, JF
Stebbing, J
Feldhahn, N
Item Type: Journal Article
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.
Issue Date: 14-Feb-2017
Date of Acceptance: 23-Jan-2017
URI: http://hdl.handle.net/10044/1/44202
DOI: https://dx.doi.org/10.1016/j.celrep.2017.01.057
ISSN: 2211-1247
Publisher: Elsevier (Cell Press)
Journal / Book Title: Cell Reports
Volume: 18
Issue: 7
Copyright Statement: © 2017 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Imperial College Trust
Leuka
Action Against Cancer
Leukaemia & Lymphoma Research "Beating Blood Cancers"
Imperial College Healthcare NHS Trust- BRC Funding
Leuka
National Institute for Health Research
CANCER RESEARCH UK
Commission of the European Communities
Leuka
Bloodwise
Funder's Grant Number: PC2821ICT
na
N/A
13016
RDB05 79560
P47415
NF-SI-0611-10275
JXR11127
630911
N/A
13016
Publication Status: Accepted
Start Date: 1687
Appears in Collections:Division of Cancer
Department of Medicine



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