3
INSIGHTS | PERSPECTIVES 1458 19 DECEMBER 2014 • VOL 346 ISSUE 6216 sciencemag.org SCIENCE D iffuse 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 ( 35). 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 1 Division of Pediatric Hematology-Oncology, Department of Pathology, and Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, 27710, USA. 2 Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, 92037, USA. E-mail: [email protected]; oren. [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 function PDGFR-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 lost Chromatin open Cancer-promoting genes expressed Methylation maintained Chromatin closed Cancer-promoting genes repressed ILLUSTRATION: V. ALTOUNIAN/SCIENCE Published by AAAS on December 19, 2014 www.sciencemag.org Downloaded from on December 19, 2014 www.sciencemag.org Downloaded from

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Page 1: For pediatric glioma, leave no histone unturned

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

ILL

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Published by AAAS

on

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Page 2: For pediatric glioma, leave no histone unturned

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).

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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

Page 3: For pediatric glioma, leave no histone unturned

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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