Oncogene (1998) 16, 2123 ± 2129
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Failure of central nervous system myelination in MBP/c-myc transgenic
mice: evidence for c-myc cytotoxicity
Niels A Jensen1, Karen M Pedersen1, Julio E Celis1 and Mark J West2
Departments of 1Medical Biochemistry and 2Neurobiology, University of Aarhus, 8000 Aarhus C, Denmark
c-myc is a member of the helix ± loop ± helix/leucine
zipper family of proteins that modulate the transcriptional activity of speci®c target genes. Although aberrant
c-myc expression has been reported to play a role in
multistage carcinogenesis in astrocytic gliomas, little is
known about the e€ects of the expression of c-myc on
oligodendrocytes. Using transgenic animals expressing a
human c-myc oncogene under transcriptional control of
the myelin basic protein gene, we investigated the e€ect
of overexpression of this oncogene in oligodendrocytes.
The MBP/c-myc transgenic mice developed severe
neurological disturbances characterized by action tremors and recurrent seizures, and premature death during
postnatal weeks three to ®ve. A€ected transgenic mice of
various strains had severely hypomyelinated central
nervous systems and expressed low levels of c-myc,
myelin basic protein (MBP) and proteolipid protein
(PLP) mRNAs in the brain. These c-myc transgenic
mice also exhibited an increased number of TUNEL
positive nuclei, which in most cases were located in cells
that expressed c-myc, as judged by double immunohistochemistry. There was no evidence of brain tumors in
the c-myc transgenic mice, including heterozygous mice
from two strains that had normal lifespans. These
observations indicate that the myelin de®ciency observed
in the MBP/c-myc transgenic animals results from a
cytotoxic e€ect of the c-myc transgene.
Keywords: hypomyelination; programmed cell death;
oligodendrocytes
Introduction
There is increasing evidence that degenerative processes
in post mitotic cells can result from aberrant cell cycle
activity triggered by a potent carcinogen (Feddersen et
al., 1992; Heintz, 1993). Because it is well established
that c-myc can induce both programmed cell death and
oncogenesis, depending on cell context (reviewed in
Amati and Land, 1994; Packham and Cleveland, 1995;
Ryan and Birnie, 1996), we designed a study that
would enable us to evaluate the e€ect of the
overexpression of this oncogene on oligodendrocytes.
Oligodendrocytic gliomas are relatively rare in that
they represent only 5 ± 15% of the gliomas diagnosed
in humans (Russell and Rubinstein, 1989; Ganju et al.,
1994). Most neuroectodermal tumors in the mature
human brain are of astrocytic origin and in anaplastic
Correspondence: NA Jensen
Received 8 September 1997; revised 21 November 1997; accepted 21
November 1997
variants, such as glioblastoma multiforme, overexpression of the cellular oncogene c-myc is common (Trent
et al., 1986). The relatively low frequency of
oligodendrocytic tumors indicates that oligodendrocytes are more resistant to neoplastic transformation
than astrocytes. In the disseminated myelin disorder
progressive multifocal leukoencephalopathy, which
results from the infection of oligodendroglia by the
oncogenic papovavirus JC, clinical symptoms appear to
be related to the loss of myelin rather than the presence
of glial tumors (Major et al., 1992; Berger and Concha,
1995). To our knowledge, there has been only one
report to date describing a relationship between the
expression of the papovavirus large T antigen and the
development of an oligo-astrocytoma and this involved
a single immunocompetent patient (Rencic et al., 1996).
The incidence of tumors expressing markers speci®c to
the oligodendrocyte lineage has been reported to be
low in transgenic mice that expressed an activated
c-neu oncogene, under control of the MBP promoter
(Hayes et al., 1992). In the 14 transgenic MBP/c-neu
strains generated, a total of ®ve brain tumors were
observed and these were con®ned to the progeny of
four strains. The ultrastructural features of cells in the
tumors were similar to those of poorly di€erentiated
cells and the light microscopic features of the tumors
did not resemble those of human oligodendrogliomas.
In contrast to the low frequency of oligodendrocytic
tumors in MBP/c-neu transgenic mice, a high frequency
of mammary adenocarcinomas was observed in
transgenic mice that expressed the neu oncogene in
mammary epithelium (Muller et al., 1988; Bouchard et
al., 1989).
Myelin is a laminar membraneous structure, laid
down in segments around selected nerve ®bers, that
increases the velocity of action potentials (reviewed in
Raine, 1984; Pfei€er et al., 1993; Morell et al., 1994;
Bunge and Fernandez-Valle, 1995; Rosenbluth, 1995;
Waxman and Black, 1995; Mirsky and Jessen, 1996;
Ransom and Orkand, 1996). The myelin of the central
nervous system (CNS) is formed by post mitotic
oligodendrocytes, which comprise a population of
structurally heterogeneous cells found primarily in the
white matter (reviewed in Szuchet, 1995). In the corpus
callosum and the optic nerve, a single oligodendrocyte
typically myelinates between ®ve and 20 axonal
internodes, whereas a one-to-one relationship is often
observed in large axons of the spinal cord (Remahl and
Hildebrand, 1990; Butt and Ransom, 1993). A number
of myelin-speci®c proteins are abundantly expressed by
di€erentiated oligodendrocytes and believed to participate in the formation of myelin (reviewed in
Campagnoni, 1995). The myelin basis protein (MBP)
gene, for example, is expressed exclusively in myelinforming cells and is believed to be involved in the
Cytotoxic effect of the c-myc oncogene
NA Jensen et al
2124
compaction of the myelin sheath. Using a transgenetic
approach, in which a human c-myc oncogene was
expressed under control of a 3 kb MBP promoter, we
show in the present study that c-myc impairs the
myelination of the CNS and that this is likely to be the
consequence of a cytotoxic e€ect that destroys cells
expressing the transgene. Our data also indicate that
c-myc has little neoplastic potential in di€erentiated
oligodendroglia.
Results
Generation and characterization of MBP/c-myc
transgenic mice
A total of ®ve transgenic mice that contained a human
c-myc oncogene under transcriptional control of the
MBP promoter were generated (Figure 1). Two MBP/
c-myc F0 transgenic mice, designated Tg2 and Tg3,
developed severe action tremors around postnatal day
10 (P10) that progressed to tonic seizures within days.
Tg2 was sacri®ced at P21 for electron microscopy. Tg3
died at P28, most likely as a consequence of seizures. A
behaviorally normal F0 mouse, designated Tg22, was
most likely a germline mosaic in that only about 1/5 of
its progeny were transgenic. All of the Tg22 transgenic
o€spring, however, developed action tremors and tonic
seizures and died within 3 ± 5 weeks, making it
impossible to establish a My22 transgenic strain. Two
transgenic mice, Tg5 and Tg23, appeared behaviorally
normal and transgenic strains, My5 and My23
respectively, were established from these founders.
Intercrossing heterozygous transgenic mice from the
My5 strain showed that 27% of the o€spring (n=38)
developed severe tremors and seizures and died within
3 ± 5 weeks. Similar experiments with heterozygous
My23 mice revealed that only about 13% of the
o€spring (n=44) developed tremors and seizures and
died prematurely.
Histochemical and electron microscopic analysis of
spinal cord and optic nerve sections revealed that the
CNS was severely hypomyelinated in a€ected transgenic mice (Figures 2b and 3b). In parallel with the
Figure 1 Generation of transgenic mice. (a) Diagram of the
endogenous human c-myc locus and the MBP/c-myc transgene.
The relevant structure of the c-myc gene, including the entire
exon-intron area is illustrated at the top. The gene structure is
presented in a 5' to 3' orientation, with exons shown as boxed
regions; the translated regions are white and the untranslated
regions are black. The transgene shown at the bottom of the
®gure contains exon 2 and 3 of the human c-myc gene ¯anked at
the 5' end by the mouse MBP promoter (3.1 kb). In order to
insure high levels of expression of the transgene, exon 1, which
contains negative regulatory elements, was removed (Xu et al.,
1991). The KpnI ± AatII fragment of MBP/c-myc was isolated
from vector sequences and microinjected into fertilized mouse
eggs to produce transgenic mice. Restriction sites are as follows:
AatII, A; ClaI, C; KpnI, K; XbaI, X
lack of central myelin in the c-myc mice, there was a
marked reduction in mRNA encoding the major
structural proteins of myelin, MBP and PLP (Figure
4). In addition, we consistently detected only minor to
moderately increased levels of c-myc gene expression in
the brains of a€ected transgenic mice derived from
distinct founders (Figure 4). Because concomitant low
expression levels of c-myc and myelin speci®c mRNAs
may re¯ect the possibility that high levels of c-myc are
cytotoxic to oligodendroglia, we TUNEL stained
(Gavrieli et al., 1992) saggital brain sections, to
determine whether or not the rate of cell death in the
CNS of MBP/c-myc transgenic mice was greater than
that of age matched controls. In transgenic animals,
the majority of TUNEL-labelled nuclei appeared as
isolated single cells in regions that corresponded to
white matter in normal animals (Figure 5a, b). At
postnatal days 14 (P14) and P21, there were two to
four times more TUNEL-labelled nuclei in the brains
of transgenic animals than in the non-transgenic
counterparts (Figure 5c). In addition, a twofold
increase in the number of TUNEL-labeled cells was
observed in a€ected transgenic mice at P14, but not at
P21 (Figure 5c). To determine whether or not the
Figure 2 Sections through cervical levels of the spinal cord
stained for myelin with Luxol Fast Blue from (a) a non-transgenic
control showing darkly stained white matter tracts; (b) a shaking
transgenic mouse of the same age, P21, showing a generalized
hypomyelination
Cytotoxic effect of the c-myc oncogene
NA Jensen et al
2125
Figure 3 Low magni®cation electron micrographs of the optic nerves from a non-transgenic control (a), showing the normal
pattern of myelinization at P23 and an age matched a€ected c-myc transgenic mouse (b ± f), showing pronounced hypomyelination.
Higher magni®cation electron micrograph of a degenerating glial cell (c) with highly condenced chromatin (n) and fragmented
nuclear membrane. The surrounding cytoplasm and cell membrane appears normal. Note the beginning of chromatin dissemination
in the cytoplasm (arrow). More pronounced stage of degeneration (d) showing dissemination of pyknotic chromatin (asterisk) and
an autophagosome containing cellular debris (arrow). Early degradation pro®le of myelin (e). Note the continuity of the dilated
outer mesaxon-like process (arrow) containing electron dense cellular debris (asterisk), with a degenerating myelin sheath (ax, axon).
Heterophagy of cell remnants by an activated microglia (f) showing con®nement of electron dense material and chromatin (asterisk)
by the cell membrane (arrow heads) and the nucleus (n) of the microglial cell. Scale bars, 2 mm (a, b); 1 mm (c, f); 0.5 mm (d); 0.2 mm
(e)
majority of TUNEL stained cells in the CNS expressed
c-myc, we double-stained sections with a human c-myc
monoclonal antibody and the TUNEL technique. As
shown in Figure 6 (white arrows), most of the TUNEL
positive cells in the subcortical white matter of an
a€ected P16 animal were c-myc positive. Only a few
TUNEL positive cells appeared to be c-myc negative
(indicated by white circles in Figure 6).
Glial cells, in various stages of degeneration, were
occasionally observed in electron micrographs of optic
nerve sections from c-myc transgenic mice, but were
not observed in the CNS of age matched controls
(Figure 3c ± f). During the early stages of degeneration,
the glial cell nuclei contained highly condensed
chromatin and a disrupted nuclear membrane, while
the cytoplasm and the cell membrane appeared normal
(Figure 3c). At more advanced stages, the cytoplasm of
degenerating cells appeared loaded with pyknotic
chromatin and lysosomal vacuoles (Figure 3d). Small
membranous spheroids were scattered around axons
and some of these appeared to be in physical contact
with outer mesaxon-like processes of degenerating
Cytotoxic effect of the c-myc oncogene
NA Jensen et al
2126
1
2
3
MBP
PLP
c-myc
β-actin
c
Figure 4 Analysis of MBP, PLP and c-myc expression by
Northern blot analysis. Total brain RNA from shaking transgenic
mice of lines Tg23 (lane 1) and Tg22 (lane 3) and from a nontransgenic control (lane 2) was isolated from P22 animals and
used in successive hybridizations with MBP, PLP, c-myc and bactin probes as indicated. Hybridization with the b-actin probe
indicates the relative amounts of total RNA (15 mg per lane)
myelin (Figure 3e). Microglia containing lysosomal
vacuoles and chromatin debris were frequently observed in the optic nerve, indicating that heterophagy
played an important role in removal of the degenerating cells (Figure 3f).
A total of 32 una€ected transgenic mice from the
My5 and My23 strains were observed closely for 12
months for signs of behavioral abnormalities. Weak
tail tremors were apparent in about 30% of the aged
mice. Macroscopic examination of the brain and spinal
cord of these animals at autopsy revealed no evidence
of tumor pathology.
Discussion
Expression of the proto-oncogene c-myc has been
linked to the development of both undi€erentiated
and di€erentiated glial cell tumors (Trent et al., 1986;
LaRocca et al., 1989; MacGregor and Zi€, 1990;
Radner et al., 1993; Hirvonen et al., 1994; Chattopadhyay et al., 1995). Oligo-astrocytomas (mixed
gliomas) are brain tumors composed of a mixture of
astrocytes and oligodendrocytes. Banerjee and collaborators examined the relationship between the
expression of c-myc and proliferating cell nuclear
antigen (PCNA) in low-grade and malignant mixed
gliomas (Banerjee et al., 1996). A positive correlation
was demonstrated between PCNA expression and cell
proliferation in both the astrocytic and the oligodendrocytic areas of malignant mixed gliomas, while a
similar correlation between c-myc and cell proliferation
Figure 5 TUNEL-labeling of degenerating cells in the brain of
MBP/c-myc transgenic mice. (a) Light micrograph of a saggital
section through the cerebellum of a shaking transgenic mouse at
P14 showing apoptotic cells con®ned to the white matter region of
a folium. The arrow points to the degenerating nucleus shown at
higher magni®cation on the left in (b). Note the neuron rich
granule cell layer which contained few if any labeled nuclei. (b)
High magni®cation of two of the apoptotic nuclei shown in (a).
(c) A graphic representation of the number of TUNEL-labeled
cells observed in 3 to 4 matched saggital sections, approximately
1 mm from the midline, of the brains of a control mouse, and
shaking and non-shaking transgenic mice from line Tg5. The
counts are shown for one individual of each of the three types of
mice at P14 and P21. Abbreviations: g, granule cell layer; w, white
matter. Scale bars, 50 mm (a); 10 mm (b)
was observed only in the astrocytic areas of the same
tumors. A likely explanation for this phenomenon is
that high levels of c-myc are cytotoxic to oligodendrocytic tumor cells.
Cytotoxic effect of the c-myc oncogene
NA Jensen et al
Figure 6 In situ TUNEL and immunostaining of a saggital brain
section from a P16 shaking transgenic mouse. (a) TUNEL-labeled
nuclei with ¯uorescein-12-dUTP. (b) Stained with an anti c-myc
antibody. (c) Superimposure of image a and b. Double labeled
nuclei are indicated by white arrows. The few TUNEL positive
nuclei (green) that do not appear to express c-myc are indicated
by white circles in the three images
Orian et al. (1994) generated a total of nine
transgenic strains of mice that harbored an activated
c-myc oncogene under transcriptional control of a
1.3 kb MBP promoter. No brain tumors were reported
in these mice, although a transient shivering phenotype, which correlated with a central myelin defect,
occurred in the progeny from one strain, designated 2 ±
50. Because the authors were unable to detect c-myc
gene expression in the 2 ± 50 transgenic mice, they
concluded that hypomyelination in the 2 ± 50 strain was
unrelated to c-myc expression that resulted from the
insertion of the transgene into the 9F2-F4 chromosomal region. A likely alternative explanation for the
absence of transgene expression in the 2 ± 50 strain is
that threshold levels of c-myc trigger oligodendrocyte
loss by programmed cell death.
In the present study, we used a 3 kb MBP promoter
because it had previously been shown that the
sequences contained within this promoter are sufficient to selectively produce high levels of transgene
expression in myelin-forming cells (Jensen et al., 1993).
Three transgenic founders and transgenic progeny
from two una€ected F0 transgenic mice developed
similar clinical phenotypes, characterized by severe
action tremors, tonic seizures and premature death.
A€ected MBP/c-myc mice died before 5 weeks of age,
most probably as a consequence of seizures and the
lack of myelin. Although transgenic mice harboring an
oncogene that has been introduced are often predisposed to the development of a characteristic type of
neoplasm, tumors in these animals generally arise
stochastically because they require spontaneous mutations in genes that collaborate with the introduced
oncogene (Adams and Cory, 1991). The lifespan of the
a€ected MBP/c-myc mice, was however, too short to
investigate the oncogenic potential of c-myc in
oligodendroglia. Therefore, heterozygous transgenic
mice from strain My5 and My23 were followed for
up to a year in order to determine whether or not
gliomas appeared in these mice at older ages. Since
these mice harbor a greater number of TUNELlabeled cells in white matter regions than nontransgenic controls, it was not surprising that a high
proportion of the mice developed neurologic de®cits
with age. Because there was no evidence of tumor
pathology at autopsy in these animals, we believe that
the tremors most likely resulted from the cytotoxic
e€ect of c-myc rather than from neoplasm. This
conclusion is strengthened by the observation that
the hypomyelination observed in the MBP/c-myc
transgenic mice at young ages also appears to be
primarily a consequence of c-myc cytotoxicity. Action
tremors in the transgenic mice were evident around
P10 and became progressively more severe during the
second and third postnatal weeks. The onset of the
neurologic de®cits in these mice correlated with an
increase in the number of TUNEL-labeled nuclei that
were present primarily in white matter regions. At
both P14 and P21, there was a greater number of
TUNEL-labeled nuclei in the brains of both a€ected
and una€ected MBP/c-myc transgenic mice than there
were in age matched controls. However, a signi®cant
increase in the number of TUNEL-labeled cells in
a€ected transgenic mice, as compared with age
matched una€ected transgenics, was only observed
prior to P21. Because there is a high rate of myelin
synthesis in mice during the second and third
postnatal weeks and because MBP expression reaches
its peak around P18 (Benjamins and Smith, 1984), a
behavioraly relevant cytotoxic loss of oligodendroglia
most likely occurred during this time period in a€ected
transgenic mice. This scenario is supported by the
observations that a€ected transgenic animals were
severely hypomyelinated at P21 and that the majority
of TUNEL positive cells in P16 animals were also
c-myc positive. Ultrastructural examination of optic
2127
Cytotoxic effect of the c-myc oncogene
NA Jensen et al
2128
nerves from transgenic mice revealed the presence of
degenerating glial cells at various stages of disintegration, which were not observed in optic nerves from
age-matched controls. The dismantling of these cells
displayed many of the morphologic features of
apoptosis including the condensation of the chromatin, dissolution of the nuclear membrane and
heterophagy of cell remnants.
Taken together, our data suggest that deregulated
expression of c-myc is cytotoxic to oligodendroglia
and, presumably because of this cytotoxic e€ect, these
specialized cells appear resistant to c-myc induced
neoplasm. Deregulated c-myc does not block differentiation of oligodendrocyte progenitor cells in vitro
(Barnett and Crouch, 1995) and, in view of these
results, it appears that the c-myc transgene exerts its
cytotoxic e€ect on di€erentiated cells. However, we
cannot de®nitively rule out the possibility that c-myc
interferes with terminal di€erentiation of oligodendroglia in vivo, and that the late precursors then undergo
apoptosis because of the failure of terminal differentiation.
Materials and methods
DNA cloning, transgenic mice, blotting and PCR analyses
To construct the MBP/c-myc transgene, a KpnI ± XbaI
fragment containing the 3 kb MBP promoter was inserted
in the 5' orientation at the KpnI ± XbaI site of a genomic
clone of the human c-myc gene (Dalla-Favera et al., 1982).
In order to insure high levels of expression of the c-myc
transgene, exon 1, which contains negative regulatory
elements, was removed (Xu et al., 1991). A KpnI ± AatII
fragment containing the MBP promoter and exon 2 and 3
of the c-myc gene was isolated from vector sequences,
diluted to 6 ng/ml in distilled water, and microinjected into
fertilized mouse eggs to produce transgenic mice as
described previously (Jensen et al., 1993).
Transgenic mice were identi®ed by slot blots, Southern
blots, and PCR analysis of DNA samples taken from tail
biopsis. For PCR analysis, the following program was used in
the thermocycler: one cycle at 968C for 5 min; 30 cycles each
at 968C for 30 s, 558C for 30 s and 748C for 3 min; one cycle
at 748C for 8 min. The following primers were used. MBP
promoter
primer:
sense-5'-GGG CCC CGC GCG TAA
CTG TGC G-3'. c-myc primer: antisense-5'-CCT CCG CCT
ACC CAA CAC CAC G. Primers to a mouse immunophilin
gene muFKBP38 (KM Pedersen and NA Jensen, unpublished) were used as a positive control for the genomic DNA
template: sense-5'-CGG ATG AAG ACA CTG GTC-3' and
antisense-5'-CAT GAG CGG GAC ACT GAG-3'.
For Northern blotting, total brain RNA was extracted by
the isothiocyanate method (Chirgwin et al., 1979), electrophoresed in formaldehyde/agarose gels, blotted onto Hybond
N (Amersham International) membranes, and hybridized
with 32P-labeled megaprime (Amersham International)
probes.
Histology and electron microscopy
For electron microscopy, the animals were deeply
anaesthetized with pentobarbital and transcardially perfused with a phosphate bu€ered solution of 1% glutar-
aldehyde and 1% paraformaldehyde (pH 7.2). The
perfused animals were immersed in the same ®xative for
2 ± 7 days. Tissue samples were post®xed in 1% osmium,
dehydrated and embedded in Epon. Ultrathin sections were
mounted on mesh grids and stained with uranyl acetate
and lead citrate.
TUNEL labeling and immunohistochemistry
Mice were perfused intracardially with 1% paraformaldehyde. The brains were removed, embedded in OCT
compound (Tissue Tek) and frozen with CO2 gas. Sections
(10 mm) were cut with a cryostat microtome and collected
on glass slides. To detect cells with fragmented DNA, we
used the TUNEL method (Gavrieli et al., 1992). Tissue
sections were air-dried and incubated with 3% H 2O2 for
5 min at room temperature (RT) to inactivate endogenous
peroxidase. The sections were washed three times in Hanks
bu€er, followed by a single wash in terminal deoxynucleotidyltransferase (TdT) bu€er (0.5 M cacodylate, pH 6.8,
1 mM C0Cl2, 0.5 mM DTT, 0.05% BSA, 0.15 M NaCl), and
then incubated for 1 h at 378C in a moist chamber with
40 mM biotin-16-dUTP (Boehringer Mannheim) and 0.5 U
TdT (Boehringer Mannheim) per ml in TdT bu€er. After
several washes in Hanks bu€er, the sections were incubated
for 1 h at 378C in Vectastain elite ABC peroxidase
standard solution (Vector Laboratories), rinsed twice in
Hanks bu€er, and stained for 10 ± 15 min at RT using the
aminoethylcarbazole substrate kit for horseradish peroxidase (Vector Laboratories). The sections were counter
stained with Mayer's hematoxylin and mounted with
Aqua-Poly/Mount (Polysciences, Inc.).
For double immunohistochemistry and TUNEL labeling,
tissue samples were removed from animals perfused with 1%
paraformaldehyde and immersed in a 30% sucrose solution
overnight at 48C. The samples were embedded in OCT
compound (Tissue Tek) and frozen with CO2 gas prior to
cryostat sectioning. Tissue sections, approximately 20 mm
thick, were collected on glass slides, washed in TdT bu€er
and incubated for 1 h at 378C in a moist chamber with 40 mM
¯uorescein-12-dUTP (Boehringer Mannheim) and 0.5 U TdT
per ml TdT bu€er. After several washes in Hanks bu€er, the
sections were incubated with the monoclonal anti human cmyc antibody mAG223 (1 : 100 dilution) for 1 h at 378C in a
moist chamber. Following several washes in Hanks bu€er,
the sections were then incubated with a rabbit anti mouse
rhodamine conjugated antibody (DAKO, Denmark) (diluted
1 : 300) for 30 min at 378C in a moist chamber. The sections
were extensively washed, mounted with Aqua-Poly/Mount
and visualized with a Olympus BX50 ¯uorescent microscope.
Photographs were taken under rhodamine and ¯uorescein
®lters. The images were superimposed to identify the doublelabeled cells.
Acknowledgements
The authors wish to thank AM Bùnsdorf, B Andersen, D
Jensen, A Meier for expert technical assistance, and Dr J
Skouv for providing plasmid pMC41 (myc). These
investigations were supported by grants from the Danish
Medical Research Council, the Danish Cancer Society, the
Alfred Benzon Foundation, the NOVO-Nordisk Foundation and the Multiple Sclerosis Society of Denmark and the
ADRC at John Hopkins University Medical School.
Cytotoxic effect of the c-myc oncogene
NA Jensen et al
2129
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