Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia.
Epigenetic dysregulation is an emerging hallmark of cancers. We developed a high-information-content mass spectrometry approach to profile global histone modifications in human cancers. When applied to 115 lines from the Cancer Cell Line Encyclopedia, this approach identified distinct molecular chromatin signatures. One signature was characterized by increased histone 3 lysine 36 (H3K36) dimethylation, exhibited by several lines harboring translocations in NSD2, which encodes a methyltransferase. A previously unknown NSD2 p.Glu1099Lys (p.E1099K) variant was identified in nontranslocated acute lymphoblastic leukemia (ALL) cell lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant ALL xenograft. Sequencing analysis of >1,000 pediatric cancer genomes identified the NSD2 p.E1099K alteration in 14% of t(12;21) ETV6-RUNX1-containing ALLs. These findings identify NSD2 as a potential therapeutic target for pediatric ALL and provide a general framework for the functional annotation of cancer epigenomes.
1] The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2].
Jacob D
JD
Jaffe
Yan
Y
Wang
Ho Man
HM
Chan
Jinghui
J
Zhang
Robert
R
Huether
Gregory V
GV
Kryukov
Hyo-eun C
HE
Bhang
Jordan E
JE
Taylor
Min
M
Hu
Nathan P
NP
Englund
Feng
F
Yan
Zhaofu
Z
Wang
E
E
Robert McDonald
Lei
L
Wei
Jing
J
Ma
John
J
Easton
Zhengtian
Z
Yu
Rosalie
R
deBeaumount
Veronica
V
Gibaja
Kavitha
K
Venkatesan
Robert
R
Schlegel
William R
WR
Sellers
Nicholas
N
Keen
Jun
J
Liu
Giordano
G
Caponigro
Jordi
J
Barretina
Vesselina G
VG
Cooke
Charles
C
Mullighan
Steven A
SA
Carr
James R
JR
Downing
Levi A
LA
Garraway
Frank
F
Stegmeier
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002648:Child; D002843:Chromatin / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000235:genetics*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D023041:Xenograft Model Antitumor Assays
D002843:Chromatin; D006657:Histones; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human