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INSIGHTS | PERSPECTIVES
1458 19 DECEMBER 2014 • VOL 346 ISSUE 6216 sciencemag.org SCIENCE
Diffuse intrinsic pontine glioma
(DIPG) is an incurable pediatric
brain tumor. About 80% of these
tumors contain mutations in genes
that encode histones (H3.3 or H3.1)
( 1, 2), proteins that package DNA
into chromatin. These mutations, which
change lysine 27 to methionine (K27M),
are believed to sequester Polycomb repres-
sive complex 2 (PRC2), which normally
represses gene expression through histone
methylation (see the figure). In the absence
of PRC2, genes that should be silent are
expressed, which is thought to drive cell
transformation ( 3– 5). However, the precise
role of histone mutations in tumorigenesis
is unclear, and strategies to target the muta-
tions remain elusive. As reported by Funato
et al. on page 1529 of this issue ( 6), as well
as by Hashizume et al. ( 7), models of K27M-
mutant DIPG can be used to elucidate the
mechanisms of transformation and to iden-
tify new approaches to therapy.
Funato et al. created a model of DIPG
by differentiating human embryonic stem
cells into neural progenitor cells, and then
transducing them with a viral vector car-
rying the gene encoding H3.3K27M. The
use of embryonic stem cell–derived neural
progenitors to model this type of glioma
is noteworthy, as the precise cell of origin
for the disease is not known [although a
neural progenitor has been proposed as a
candidate ( 8)]. Remarkably, H3.3K27M ex-
pression was mitogenic only in neural pro-
genitors derived from embryonic stem cells,
and not in undifferentiated embryonic stem
cells or astrocytes derived from these cells.
This suggests that the histone mutation is
oncogenic only in the appropriate cell type.
In studying how H3.3K27M promotes
tumorigenesis, Funato et al. found that
the histone mutation alone was not suffi-
what cellular context, may be required for
the development of high-grade DIPG.
Although K27M mutant tumors are ini-
tiated in neural progenitors, they have an
expression profile that resembles the neural
plate–neural rosette stage, which precedes
the emergence of neural progenitor cells.
Based on this, the authors suggest that the
K27M mutation acts in part by promoting
dedifferentiation to a more primitive, stem-
like state. In particular, the authors found
that expression of the stem cell–associated
genes LIN28B, PLAG1, and PLAGL1 is up-
regulated by H3.3K27M, and that reducing
expression of these genes inhibits tumor
cell growth.
Funato et al. also carried out a small-
molecule drug screen and discovered that
antagonists of menin are potent inhibitors
of tumor growth. Menin was originally de-
scribed as a tumor suppressor in patients
with multiple endocrine neoplasia type 1,
a disorder characterized by benign tumors
in the parathyroid, pancreas, and pituitary
glands. It also functions as an oncogenic
For pediatric glioma, leave no histone unturned
Histone methylation and tumor growth. K27M histone mutants sequester PRC2, allowing loci that are normally
repressed to be activated. Mutant histones cooperate with other mutations [those that inhibit TP53 expression or
increase the activity of platelet-derived growth factor receptor A (PDGFR-A)] to promote tumorigenesis. A demethylase
inhibitor restores repressive histone marks and blocks tumor growth. Me, methylation
Examining histone mutations points to possible therapies for a lethal brain tumor
CANCER
1Division of Pediatric Hematology-Oncology, Department of Pathology, and Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, 27710, USA. 2Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, 92037, USA. E-mail: [email protected]; [email protected]
By Oren J. Becher 1 and
Robert J. Wechsler-Reya 2
cient to transform neural progenitor cells
into tumors. Only when progenitors also
expressed an activated form of platelet-
derived growth factor receptor A and
lacked the TP53 tumor suppressor could
they give rise to gliomas after injection into
the brainstem of mice. Moreover, even with
all three genetic alterations present, the
tumors grew slowly and lacked histologi-
cal features of high-grade glioma (necro-
sis and vascular proliferation). Although a
subset of K27M mutant human DIPGs are
low-grade ( 9), these observations raise the
question of what additional mutations, or
Normal
Gene expression
TP53 functionPDGFR-A activity
Tumorigenesis
DNA
Histone
PRC2
PRC2
PRC2
Me
MET
LYS
Cancer therapy
Me
K27M-mutant
histone
Me Me
Cancer
Some histones methylated by PRC2
Chromatin closed
Cancer-promoting genes repressed
PRC2 sequestered
PRC2
Demethylase inhibitor
PRC2-mediated methylation lostChromatin openCancer-promoting genes expressed
Methylation maintainedChromatin closedCancer-promoting genes repressed
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19 DECEMBER 2014 • VOL 346 ISSUE 6216 1459SCIENCE sciencemag.org
10.1126/science.aaa3814
cofactor in hematologic malignancies con-
taining mixed-lineage leukemia (MLL) gene
fusions ( 10). In both disorders, menin acts
by regulating MLL-mediated histone meth-
ylation ( 11, 12), which may explain why
inhibitors of menin counteract the onco-
genic effects of K27M mutations. Although
the role of menin in DIPG is unclear, these
studies suggest it may be an important
therapeutic target.
Hashizume et al. took a different ap-
proach to identify therapies for K27M-
mutant DIPG. They hypothesized that the
global loss of histone methylation induced
by the K27M mutation (and the resulting
sequestration of PRC2) is critical for tumor
maintenance. The authors used patient-
derived DIPG cell lines (established from
biopsies and passaged in vivo) to evaluate
the effects of a K27 demethylase inhibitor
on tumor cells. Treatment of H3.3K27M-
mutant DIPG cells with this inhibitor in-
creased H3K27 methylation and decreased
cell growth. By contrast, treatment of cells
harboring wild-type H3.3 or a different his-
tone mutation (H3.3G34R/V) had little ef-
fect. This suggests that global loss of H3K27
methylation may be the primary mecha-
nism of K27M-driven gliomagenesis and
raises the possibility that demethylase in-
hibitors may be valuable therapeutic agents
for the disease.
The discovery of K27M mutations was an
important step forward in understanding
DIPG and promises to yield new approaches
to treating the disease. The studies of Funato
et al. and Hashizume et al. take us closer to
that goal, creating models that can be used
to study DIPG biology and demonstrating
that these models can be useful for identi-
fying therapies. It will be interesting to see
whether these therapies synergize with one
another, or with focal radiation, the stan-
dard of care for children with DIPG. Given
the dismal prognosis associated with this
disease, there will be strong incentive to
move them forward into clinical trials. ■
REFERENCES
1. G. Wu et al., Nat. Genet. 44, 251 (2012). 2. J. Schwartzentruber et al., Nature 482, 226 (2012). 3. P. W. Lewis et al., Science 340, 857 (2013). 4. S. Bender et al., Cancer Cell 24, 660 (2013). 5. K. M. Chan et al., Genes Dev. 27, 985 (2013). 6. K. Funato, T. Major, P. W. Lewis, C. D. Allis, V. Tabar, Science
346, 1529 (2014). 7. R. Hashizume et al., Nat. Med. 10.1038/nm.3716 (2014). 8. M. Monje et al., Proc. Natl. Acad. Sci. U.S.A. 108, 4453
(2011). 9. P. Buczkowicz, U. Bartels, E. Bouffet, O. Becher, C.
Hawkins, Acta Neuropathol. 128, 573 (2014). 10. A. Yokoyama et al., Cell 123, 207 (2005). 11. S. K. Karnik et al., Proc. Natl. Acad. Sci. U.S.A. 102, 14659
(2005). 12. Y. X. Chen et al., Proc. Natl. Acad. Sci. U.S.A. 103, 1018
(2006).
ILL
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Nanovesicles known as exo-
somes are secreted from a
variety of cell types and cir-
culate in biological fluids
such as urine and plasma.
These exosomes “hijack”
membrane components and cy-
toplasmic contents of these cells
and play an important role in in-
tercellular communication, often
inducing physiological changes
in recipient cells by transferring
bioactive lipids, nucleic acids, and
proteins ( 1). These tiny vesicles
also have been implicated in a
number of human diseases, in-
cluding cancer, and are becom-
ing an appreciated fundamental
aspect of tumor progression and
metastasis ( 2). Recently, Melo
et al. ( 3) showed that exosomes
from breast cancer cells transfer
microRNAs (miRNAs) to normal
cells and stimulate them to be-
come cancerous. This potentially
expands the mechanisms by
which cancer spreads and may
provide opportunities to develop
exosome-based diagnostics and
therapies.
Many physiological processes
involve exosomes, such as cell growth, neu-
ronal communication, immune response ac-
tivation, and cell migration, and in the case
of cancer, may transfer angiogenic proteins
or oncogenes from one cell to another ( 4– 7).
Thus, analyzing the macromolecules har-
bored by exosomes could have important
diagnostic and therapeutic implications. Ex-
perimental evidence shows that exosomes
mediate interactions between cancer and
normal cells. For example, exosomes secreted
by breast cancer cells inhibit exosome release
from the normal counterparts. These cancer
exosomes may trigger extracellular acidity
in which cancer cells (but not healthy cells)
can survive and which activates hypoxia-
dependent angiogenesis during tumor devel-
opment ( 1). Exosomes can also induce drug
resistance of cancer cells by sequestering
chemotherapeutic agents (8); and can stimu-
late metastasis ( 2).
Interestingly, exosomes contain messen-
ger RNA (mRNA) and miRNA that can be
transferred to other cells and regulate gene
expression of the target cell ( 9). Likewise,
miRNAs are present in apoptotic bodies
(small membrane vesicles that are pro-
duced by cells undergoing programmed cell
death) ( 10), or they are in the plasma, as-
sociated with Argonaute2 (AG02), the key
effector protein of a miRNA-mediated gene
silencing mechanism ( 11). However, miR-
NAs detected in human serum and saliva
are mostly concentrated inside exosomes
( 12). Virally encoded miRNAs are also
found in exosomes, indicating how onco-
genic viruses could manipulate the tumor
microenvironment ( 13).
Malicious exosomes
Primary
miRNA
Precursor
miRNA
Target
recognition
Dicer
Mature
miRNA
TRBP
RISC
AGO2
RISC
AGO2
Translationally repressed mRNA
Nucleus
Cytoplasm
MiRNA biogenesis. MiRNAs combine with AGO2 and other proteins
in an RNA-induced silencing complex (RISC) to repress the translation
of target mRNAs.
By Eleni Anastasiadou and
Frank J. Slack
Nanovesicles derived from cells of cancer patients carry microRNAs that initiate tumor growth in normal cells
CANCER
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. E-mail: [email protected]
Published by AAAS
DOI: 10.1126/science.aaa3814, 1458 (2014);346 Science
Oren J. Becher and Robert J. Wechsler-ReyaFor pediatric glioma, leave no histone unturned
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