Lineage-specific genes are prominent DNA damage hotspots during leukemic transformation of B-cell precursors
File(s)
Published version
Author(s)
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.
-
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.
Date Issued
2017-02-14
Date Acceptance
2017-01-23
Citation
Cell Reports, 2017, 18 (7), pp.1687-1698
ISSN
2211-1247
Publisher
Elsevier (Cell Press)
Start Page
1687
End Page
1698
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
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
Grant Number
PC2821ICT
na
N/A
13016
RDB05 79560
P47415
NF-SI-0611-10275
JXR11127
630911
N/A
13016
Publication Status
Published
Start Date
1687