From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
MYC Rearrangements in Histologically Progressed Follicular Lymphomas
By Takahiro Yano, Elaine S.Jaffe, Dan L. Longo, and Mark Raffeld
Histologic transformation of low-grade follicular lymphoma
t o an aggressive-grade lymphoma occurs in 60% to 80% of
patients during their clinical course. The events that drive the
transformation process are poorly understood. Deregulation
of the MYC gene has been implicated in a small number of
cases. This observation led us t o examine the molecular
organization of the MYC oncogene in 38 cases of histologically transformed lymphomas that arose from follicular lymphomas, and in 18 of the initial pretransformation follicular
lymphomas. In addition, we examined 58 “control” lowgrade follicular lymphomas that had not yet shown evidence
of histologic progression. Immunoglobulin heavy chain and
light chain gene rearrangements were detected in all biopsies and rearrangements of the BCL-2 locus were seen in 36
of 38 of the transformed lymphomas (consistent with their
origin from follicular lymphomas), in 18 of 18 of the pretransformation follicular lymphomas, and in 51 of 58 of the control
follicular lymphomas. All 18 pretransformation follicular lymphoma specimens displayed at least one immunoglobulin
gene and BCL-2 rearrangement in common with the corresponding histologically progressed lymphoma, indicating a
clonal relationship between the original follicular lymphoma
and the histologically transformed lymphoma. MYC rear-
rangements were detected in 3 of 38 (8%) transformed
lymphomas and in 1 of 58 (2%) control follicular lymphomas.
The latter MYC rearranged follicular lymphoma was clinically
aggressive and transformed t o a high-grade lymphoma that
led t o the death of the patient within 20 months. None of the
18 pretransformation follicular lymphomas showed MYC
rearrangement, including t w o from patients who later demonstrated MYC rearrangement in the progressed aggressive
lymphoma. hull mutational analysis failed t o identify additional MYC gene abnormalities in the progressed lymphomas. Because the Epstein-Barr virus (EBV) is associated with
a fraction of high-grade lymphomas and is known t o upregulate BCL-2, we looked for a potential role for this agent in our
progressed lymphomas. We did not detect viral sequences in
any case indicating that EBV does not play a major role in
progression. The presence of MYC rearrangements in a small
fraction of progressed aggressive lymphomas, and not in the
corresponding antecedent follicular lymphomas, suggests
that acquisition of a MYC rearrangement is in some cases
associated with the transformation event.
This is a US government work. There are no restrictions on
its use.
F
secondary chromosomal abn~rmalities.~*-~~
Although some
of these secondary chromosomal aberrations tend to recur,
none accounts for an appreciable fraction of the total
abnormalities, and the cytogenetic data to date do not
suggest a predominant genetic locus responsible for histologic transformation.
One candidate gene that may play a role in the transformation process is the MYC oncogene on chromosome 8q24.
The MYC protein has been shown to be a member of the
leucine zipper family of DNA-binding proteins and has
been implicated as a potent regulator of cellular proliferation.16J7 Experimentally, the MYC gene has been shown to
act synergistically with the BCL-2 gene both in transfection
studied8 and in transgenic mouse models, where it has been
shown to be altered in 50% of the high-grade tumors arising
in mice with BCL-2 trans gene^.^^,*^ Clonal rearrangements
of the MYC oncogene, the hallmark of sporadic Burkitt’s
lymphoma, have also been reported in a fraction of diffuse
large-cell lymphoma^.^^-^^ More interestingly, there have
been several cases of high-grade lymphomas or lymphoid
leukemias carrying both a t( 14;18) translocation and a
t(8;14), t(2;8) or t(8;22) translocation that have involved the
MYC and BCL-2 l o ~ i . Some
~ - ~ ~of these patients had
documented evidence of a prior or coexisting low-grade
follicular lymphoma. This observation suggests that in these
cases the low-grade lymphoma containing the BCL-2 rearrangement acquired a second genetic alteration involving
the MYC oncogene, resulting in its transformation to a
diffuse high-grade lymphoma or an acute leukemia. Chromosomal translocations involving 8q24 and chromosomal
loci other than those associated with the Ig genes have also
been r e p ~ r t e d in
~ ~aggressive
-~~
lymphoproliferative diseases and include the t(8;17) translocation, the site of the
recently described BCL-3 gene.39In this latter case, MYC
involvement was not suggested by cytogenetic studies
OLLICULAR LYMPHOMA accounts for approximately 50% of all non-Hodgkin’s lymphomas occurring in adults in the United States. Despite advanced-stage
disease, patients with follicular lymphoma have a relatively
favorable prognosis. However, histologic conversion to a
more aggressive diffuse lymphoma occurs in a high percentage of patients (59% to 78%) during their clinical course.14
This transformation is associated with increased clinical
aggressiveness of the lymphoma and a poor prognosis even
with intensive treatment.5-7The underlying genetic basis for
this histologic transformation is not known.
The t( 14;18)(q32;q21) translocation is detected in up to
90% of follicular lymphomas8 This event juxtaposes the
bcl-2 proto-oncogene to the Ig heavy chain joining region
and leads to its overexpression>Tl0Overexpression of bcl-2
is believed to promote lymphomagenesis, as the protein has
been implicated as an inhibitor of programmed cell death.”
Cytogenetic studies indicate that follicular lymphomas
which undergo histologic transformation retain their t( 14;
18) translocation and generally acquire multiple, complex
From the Laboratory of Pathology, Division of Cancer Biology,
Diagnosis and Centers, National Cancer Institute, Bethesda, MD; and
the Biological Response Modijiers Program, Division of Cancer
Treatment, National Cancer Institute-Frederick Cancer Research and
Development Center, Frederick, MD.
Submitted February 7, 1992; accepted April 9, 1992.
Address reprint requests to Mark Raffeld, MD, Hematopathology
Section, Laboratory of Pathology, Bldg IO, Room 2Nll0, National
Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
The publication costs of this article were defiayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section I734 solely to
indicate this fact.
This is a US govemment work. There are no restrictions on its use.
0006-497119218003-0022$0.00/0
758
Blood, VOI 80, NO3 (August 1). 1992: pp 758-767
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
MYC REARRANGEMENTS IN PROGRESSED LYMPHOMAS
and was only identified using molecular techniques. Observations such as these have led a number of investigators to
postulate a potential role for the MYC gene in tumor
progression.30
Thus, to assess the role of the MYC oncogene in histologic progression, we examined its molecular organization
in 38 cases of histologically transformed lymphomas, in 18
matched pretransformation follicular lymphomas, and in 58
“control” cases that consisted of follicular lymphomas that
had not yet shown evidence of progression. We identified
MYC rearrangements in three transformed lymphomas and
in one unusually aggressive control follicular lymphoma,
and describe in detail the pattern of involvement of the
MYC gene in these cases.
MATERIALS AND METHODS
Materials Studied and Diagnostic Criteriafor Histologic
Transformation
Thirty-eighthistologically transformedfollicular lymphomas from
patients observed at the National Institutes of Health were
selected for this study based on the availability of frozen tissue for
the molecular analyses and a pretransformation biopsy documenting a prior diagnosis of low-grade follicular lymphoma. In 18of the
38 patients, frozen tissue was also available on the matched
pretransformation follicular lymphoma. An additional 58 randomly
selected low-grade follicular lymphomas that had not yet undergone histologic transformation were also studied as controls. All
patients in this study are part of ongoing clinical studies and have
provided informed consent according to the guidelines of the
Institutional Review Board of the National Institutes of Health.
All lymphoma diagnoseswere classified according to the International Working Formulation for Clinical Usage.@ A follicular
lymphoma was considered low grade if it was diagnosed as a
follicular small cleaved cell lymphoma or a follicular mixed small
cleaved and large cell lymphoma. It was considered to be histologically transformed if on subsequent biopsy any of the following
histologies were seen: follicular large cell (FL), diffise mixed
(small cleaved and large cell) (DM), diffuse large cell (DL), large
cell immunoblastic (IBL), or small noncleaved cell (SNC) lymphoma. The histology of the transformed tumors included two FL,
eight DM, 26 DL, and two SNC (Table 1).
Immunohistochemistryfor Suface Igs and Terminal
TransferaseActivity of the Tumor Cells
Neoplastic cells from biopsies of involved lymph nodes or other
tissues, ascitic or pericardial fluid were prepared and stained with a
panel of monoclonal antibodies that included anti-y, anti-al,
anti-a2, anti-6, anti-K, and anti-A Igs (Becton Dickinson, Monoclonal Antibodies, Mountain View, CA) and anti-p Ig (Bethesda
Research Laboratories [BRL], Gaithersburg, MD) for analysis by
flow cytometry and immunohistochemistry as previously described?l The presence of immunoreactive terminal transferase
(Tdt) was assessed on frozen sections of MYC rearranged cases
using a cross-reactingrabbit anti-bovine Tdt antibody (BRL) by an
avidin-biotin-peroxidasemethod.42
MolecularAnalysis
Southem blot hybridization. High-molecular weight DNA was
isolated directly from involved frozen tissue samples or cell
suspensions as described previ0usly.4~After restriction enzyme
digestion with HindIII, EcoRI, BumHI, PstI, XbaI, &nI, PvuII,
SstI, SmuI, or Hue111 (BRL), the DNA was size-fractionated by
759
Table 1. Histologic Diagnoses and Summary of Molecular Results
Chromosome 18 Breakpoints
Diagnosis
No. of
Cases‘
Not
mbr
mcr 5 BCL-2 Identified
Transformed lymphomas
Follicular large cell 2 (O)* 0 (0) 2 ( 0 )
Diffuse mixed cell 8 (4) 5 (2) 3 (2)
Diffuse large cell 26 (13)19 (10) 5 (3)
Small noncleaved
2 (1) l(0) l(1)
cell
Total
38 (18)25 (12)1 1 (6)
Nontransformed lymphomas
Low-grade
follicular
58
37
lymphomas
13
MYC
Rearrangement
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
2 (0)
0 (0)
0 (0)
2 (0)
0 (0)
0 (0)
0 (0)
2 (0)
l(0)
3 (0)t
1
7
I*
‘Numbers in parentheses are the results for the available antecedent
low-grade follicular lymphomas.
tlncluded in the 18 antecedent low-grade follicular lymphomas
studied for MYC rearrangement are two of the three cases in which the
progressed lymphomas showed MYC rearrangement. One of the three
was not available for molecular analysis.
*Despite its low-grade histology, this lymphoma pursued an aggressive clinical course, resulting in the patient’s death in 20 months.
Autopsy showed progression to a diffuse large cell lymphoma (not
available for molecular analysis).See case 4 in Results and Table 2.
agarose gel electrophoresis and transferred to nylon membranes
(Gene Screen Plus, New England Nuclear Research Products,
Boston, MA; or Zeta-Probe, Bio-Rad, Los Angeles, CA). The
filters were serially hybridized with random primed 32P-labeled
probes for 16 to 24 hours at 42°C and washed under stringent
conditions according to the instructions supplied for Gene Screen
Plus. Autoradiographs using Kodak X-Omat AR films (Eastman
Kodak, Rochester, NY)were developed after 1 to 7 days.
DNA probes. Four different probes were used to assess the
configuration of the MYC gene and are shown in Fig 1. The third
exon probe, a 1.4-kb CluIIEcoRI fragment, was used for screening
of MYC rearrangements. The other three probes, the 5’ first exon
probe (1.1-kb HindIII/ClaI fragment), the first exon probe (0.9-kb
PvuII fragment), and the second exon probe (0.4-kbPstI fragment),
were used for mapping chromosome 8 breakpoints in cases with
MYC rearrangements. The first exon probe was also used to detect
potentialPvuI1 site mutations in the first exon (discussed below).
BCL-2 gene probes included bcl-2 (BCL-2 mbr), pFL 2 (BCL-2
mcr), and pB16 (5’ BCL-2). The two Epstein-Barr virus (EBV)
terminal repeat probes used were a 1.9-kb XhoI fragment and a
2.8-kb EcoRI fragment.44The molecular organization of Ig gene
loci was investigated using six heavy-chain gene probes and three
light-chain gene probes as described previously$5 and include
probes to JH, Sp, Cp, Cy4, Cal, CE,JK,CK,and Ch.
Mupping of chromosome 8 breakpoints. The location of chromosome 8 breakpoints was mapped by sequential hybridizations of
two or more digests with the each of the three MYC probes. If the
rearranged bands detected with any two of the MYC gene probes
differed in size in the same restriction enzyme digest, the breakpoint was considered to lie between the two probes. A breakpoint
was considered to lie within a probe sequence if two MYC
rearrangements were identified in two or more digests. If all three
MYC probes showed the same rearrangement in Hind111 digest and
no rearrangement in EcoRI digest, the chromosome 8 breakpoint
was assigned 3‘ to the MYC gene (EcoRI-Hind111 fragment). The
absence of the rearrangement with the 5’ first exon probe despite
the presence of the same rearrangement with the other two probes
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
YANO ET AL
II
I
EXONS
- -
- -
PROBES
9’EXoNI
EXONII
EXON1
1
BREAKPOINT LOCATIONS
*
Ill
2
4
in more than two enzyme digests was attributed to a deletion of
sequences located 5 ’ to the chromosome 8 breakpoint including at
least the 5’ first exon probe sequence.
Evaluation of restriction enzyme site mutations in the MYC gene.
In cases with chromosome 8 breakpoints occurring far 5’ or 3’ to
theMYC locus, it is not possible to detect their breakpoints directly
using conventional probes. However, most Burkitt’s lymphomas
that have these classes of breakpoints also have mutations near the
3’ boundary of the MYC first e ~ o n . ~These
- ~ ’ are particularly
common at the PvuII site. Therefore, by evaluating the status of
this PVuII site, it is possible to look indirectly for evidence of MYC
involvement. For this purpose, PvuII-digested DNA was probed
with the first exon probe. Tumors were assessed positive for the
PvuII site mutations if a novel 1.8-kb fragment appeared with a
corresponding decrease in intensity of the normal 0.9-kb germline
fragment. PstI, SstI, or HaeIII digests were also used to look for
possible mutations in the MYC locus of some tumors in combination with our MYC probes.
Assignment of the breakpoints in the Iggene loci. Breakpoints in
the JH locus were identified by comigration of a JH rearrangement
with a MYC or BCL-2 fragment in two or more digests. Comigration of the S p fragment with a MYC fragment indicates the break
has occurred within or near any one of several switch loci including
Sp, Sa, Se, and, under some conditions, Sy, because of the
homology of the Sp probe sequence to the other switch loci.
Additional comigration studies using specific constant region
probes (Cp, Cy, GI,or Ce) with the appropriate enzyme digests
showed which switch loci were involved in the translocations. In
those cases where we could not demonstrate comigration with an Ig
heavy-chain gene fragment, potential light-chain gene comigration
was studied using the appropriate enzyme and probe combinations.
RESULTS
Molecular Organizationof Ig Gene and 18q21 Loci
Thirty-eight histologically transformed lymphomas from
patients with a prior diagnosis of low-grade follicular
lymphoma were studied (Table 1). Ig heavy and light chain
gene rearrangements were detected in all 38 biopsies.
Thirty-six of the 38 (95%) showed rearrangement of the
BCL-2 locus, consistent with their derivation from follicular
lymphoma. Chromosome 18 breakpoints occurred within
the major breakpoint region (mbr) in 25 tumors and within
the minor cluster region (mcr) in 11 tumors. All 18q21
rearrangements except for two mcr rearrangements comigrated with a JH rearrangement, indicating t(14;18) translocation.
In 18 of the 38 progressed cases, DNA samples from the
original low-grade follicular lymphoma were also available
for study. All 18 displayed at least one JH rearrangement in
EXONIII
3
Fig 1. Restriction map of the
human MYC locus. Relevant restriction sites, probe fragments,
and the breakpoint locations of
the four MYC rearranged cases
are included. E, EcoRI; H, Hindlll;
P, h u l l ; P*, hypermutableh u l l
site in the first exon. Open and
closed rectangles represent noncoding and coding regions of exons, respectively.
common with the corresponding progressed tumor, as well
as an identical BCL-2 rearrangement consistent with the
expected clonal relationship between the two. However,
nine of the 18 exhibited a monoallelic alteration of the size
of the JH rearrangement. This has been previously observed by us43and other^^^,^^ and is believed to be due to
ongoing mutations.in the Ig heavy chain locus.
A n additional 58 control follicular lymphomas that had
not yet undergone histologic transformation were also
studied. All showed JH rearrangements, and 51 of the 58
(88%) had BCL-2 locus rearrangements. The incidence of
BCL-2 rearrangement in the control group is not statistically different from that found in the progressed follicular
lymphomas (P > .45, Fisher’s exact test). Chromosome 18
breakpoints occurred in the mbr in 37 cases, in the mcr in 13
cases, and in the 5’ BCL-2 region in one case. All 18q21
rearrangements with the exception of three mcr rearrangements comigrated with a JH rearrangement.
The frequencies of mbr and mcr BCL-2 breakpoints is
similar to that previously reported in the literature by
several groups for follicular lymphoma^.^^^^
Involvement of the MYC Oncogene
MYC gene rearrangement was observed in 3 of the 38
(8%) transformed lymphoma specimens (cases 1,2, and 3;
Tables 1 and 2) using a combination of the three described
MYC gene probes covering exons I through 111. None of the
18 matched pretransformation low-grade follicular lymphomas showed MYC gene rearrangement, including two of the
three cases that subsequently displayed a MYC rearrangement in the corresponding progressed lymphoma sample.
Somewhat unexpectedly, 1 of the 58 control follicular
lymphomas was found to have a MYC gene rearrangement.
However, this case proved to be clinically aggressive and
unresponsive to treatment, and the patient died 20 months
later with disseminated diffuse large cell lymphoma. Tissue
from the autopsy was not available for study.
Because the PvuII site mutations in the first exon are
often associated with MYC translocations that lie outside of
the regions covered by our probes (ie, far 5’ or 3’ to the
MYC gene exons), we also probed for the presence of this
mutation. None of the 38 cases showed PvuII site mutation.
Role of EBV in Tumor Progression
EBV is associated with high-grade lymphoproliferative
disorders, including virtually all cases of endemic Burkitt’s
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
MYC REARRANGEMENTSIN PROGRESSED LYMPHOMAS
761
Table 2. Summary of MYC Rearranged Cases
Case
Histologic
Diagnosis
1
FSC
ND
DL
FSC
SNC
2
Gene Rearrangements
Surface
No.
Chromosome 8
JH
JK
CA
18q21
R i Rz
RIRY
G(D)
R
R(mbr)
NA
-
Negative
G(D)
R
R(mbr)
-
lgMX
NI
RIRZ
RlRi*
G(D)
G(D)
R
R(mcr)
2R (mcr)
First exon and its
flanking region
(Clal-Pvull)
NA
Firstintron
Igs
R
Breakpoint
EBV
-
(hull-Pstl)
3
DL
lgMK
R i Rz
2R
G
2R (mbr)
4
FSC
lgMK
RiRz
R
G
R (mcr)
3' to exon 111
(hull-Xbal)
First intron
(sSmal-Pstl)
-
Comigration
Study
mbr = JH(Rl)
mbr = JH(R,)
c-myc = JH(R;) = Cy
mcr = JH(Rl)
mcr = JH(Rl)
c-myc = Swt
c-myc = CE,Ca
5MYC = JH(Rb)
mbr = JH(Rl)
c-myc = none
mcr = none
c-myc = none
Abbreviations: ND, not done; NI, not interpretable; NA, not applicable; R, rearranged; G, germline.
*Rl and R2 refer to each of the two original JH alleles. Rk refers to a new second JH restriction fragment, which appeared in the transformed
biopsies of cases 1 and 2 and was associated with loss of the R, that was present in the antecedent follicular lymphoma.
tSp probe cross-hybridizeswith SEand Sa.
lymphoma:* a high fraction of lymphomas occurring in
immunodeficiency setting^:^-^^ and a smaller fraction of
nonimmunodeficiency-related sporadic Burkitt's lymphomas and diffuse large-cell lymphoma^.^^.^^ It has also been
shown to alter the regulation of the follicular lymphomaassociated oncogene, BCL-2.56 We looked for viral sequences in 37 of the 38 progressed cases to determine if this
lymphotropic virus might play a role in tumor progression.
Epstein-Barr viral DNA was not detected in any of the
progressed lymphomas, excluding this agent from playing a
significant role in the transformation process.
Detailed Analysis of the Four MYC Translocated Tumors
Case 1. (Fig 2A,Table 2)This case was diagnosed as a
follicular lymphoma of small cleaved cell type in 1973 and
progressed to a diffuse large cell lymphoma in 12 years. The
patient died 6 months after histologic progression. Biopsies
from both time points were available for study. The original
follicular lymphoma showed biallelic JH rearrangements,
one of which comigrates with a BCL-2 mbr rearrangement.
No MYC rearrangement was present at diagnosis. The
transformed tumor showed the same BCL-2 mbr/JH comigration pattern as seen in the original follicular lymphoma.
The second J H allele that was present in the original
lymphoma had been lost at transformation and in its place
was a new JH rearrangement that shows comigration with a
new MYC rearrangement in the HindIII restriction digest.
A rearranged heavy-chain y locus gene segment showed
comigration with the altered MYC allele in the transformed
lymphoma in the EcoRl and BamHl digest, but not in the
HindIII digest. These patterns of comigrations suggest that
the MYC gene rearranged 5' to or directly into the JH region of a y rearranged allele in the original low-grade
tumor. Probes to both the MYC first and third exons hybridized to the same nongermline band. No rearrangement was
detected with the 5' first exon probe, suggesting that
deletion of genetic material 5' to the breakpoint occurred in
the translocation process. The chromosome 8 breakpoint
mapped to the ClaI-PvuII fragment, which corresponds to
the 5' flanking region of the first exon of the MYC gene.
Immunophenotypic analysis of the progressed lymphoma
showed an absence of surface Ig, as would be expected with
both immunoglobulin heavy chain gene alleles involved in
interchromsomal rearrangements (BCL-2 andMYC). Immunodetectable Tdt was not present.
Case 2. (Fig 2B, Table 2) This case was diagnosed as a
follicular lymphoma of small cleaved cell type and progressed after 12 years to a composite tumor composed of
low-grade follicular lymphoma and high-grade diffuse lymphoma of small-noncleaved cell type. The patient died 13
months after histologic progression. Biopsies from both
specimens were available for study. The original follicular
lymphoma showed biallelic JH rearrangements, one of
which comigrated with a BCL-2 mcr rearrangement. MYC
rearrangement was not observed in this specimen. The
transformed tumor showed the same BCL-2 mcr/JH rearrangement pattern as seen in the original follicular lymphoma. Rearrangement of MYC was present and showed
comigration with rearrangements of Sp,, CE, and Ca,
suggesting that the translocation took place during an
abortive attempt at switch recombination into the E heavy
chain constant region. The 5' first exon MYC probe detected a fragment that comigrated with J H in BamHI and
EcoRI digests (not shown). The chromosome 8 breakpoint
mapped to the PvuII-PstI fragment corresponding to the
first intron of the MYC gene, severing the transcriptional
unit from its 5' regulatory elements. Thus, MYC involvement in this case appeared similar in all respects to the form
of involvement that is commonly seen in sporadic Burkitt's
lymphoma. Interestingly, this was the only case classified as
a small noncleaved cell lymphoma.
Immunophenotypic analysis showed the original follicular lymphoma to have surface expression of IgMh, while no
surface Ig could be detected on the high-grade component
of the progressed lymphoma. Immunodetectable Tdt was
absent from the progressed tumor.
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
YANO ET AL
762
F T
F T
F T
BFT
F T
p--
a
B C L-2
MYC .
exonlll
JH
mbr
B C L-2
Hindlll
Hindlll
T
T
T
4
JH
mcr
@
F+
F"
MYC
5' exonl
F"
x'
.
( r -
.et0
.
.
.,
b
J
Q,-
a* 1
BC L-2
mbr
JH
8 C L-2
mcr
MYC
exonl II
JH
EcoRl
Hindlll
Figure 2
MYC
exonlII
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
763
MYC REARRANGEMENTS IN PROGRESSED LYMPHOMAS
Case 3. (Fig 2C, Table 2) This case was initially diagnosed as a follicular lymphoma of small cleaved cell type
and progressed in 15 years to a diffuse lymphoma of large
cell type. The patient died 16 months after histologic
progression. Tissue from only the progressed sample was
available for study. The progressed tumor showed two JH
rearrangements. One showed comigration with a rearranged BCL-2 mbr fragment, while the other (presumably
the functional allele) showed wmigration with the Ig Cp
heavy chain gene segment. Rearrangement of the MYC
oncogene was present, but there was no comigration with
any Ig heavy or light chain gene segment examined,
including JH, Sp, Cp, Cy4, Cal, CE,JK, CK, and CX. This
raises the possibility that non-Ig locus may be involved. The
chromosome 8 breakpoint mapped 3' to the MYC coding
exons (PvuII-BuI fragment). This location eliminates truncation of the MYC gene as a potential mechanism for
deregulation and suggested that the mechanism of MYC
deregulation may be mutation of the 5' regulatory sites in
the first exon. However, digestions with a battery of
enzymes, including PvuII, PstI, SstI, and HueIII, failed to
identify loss of these restriction sites (data not shown).
Thus, a potential mechanism of MYC deregulation could
not be implicated.
Immunophenotypic analysis showed expression of IgMK;
immunodetectable Tdt was absent.
Case 4. (Fig 2D, Table 2) This case was the nontransformed follicular lymphoma in which a MYC rearrangement was identified. Although morphologically this follicular lymphoma did not appear unusual, the patient had an
unusually aggressive wurse and died 20 months following
his initial biopsy with disseminated, histologically transformed, diffuse large cell lymphoma. Only the initial follicular lymphoma biopsy was available for study. This biopsy
displayed two JH rearrangements. Rearrangements of both
the BCL-2 mcr and the MYC gene were present; however,
neither showed comigration with JH nor any of the other Ig
gene fragments examined (Sp, Cp, Cy4, C d , CE, JK, CK,
and Ch). This finding, similar to that in case 3, again raises
the possibility that a non-Ig gene may be involved. The
chromosome 8 breakpoint mapped to the SmuI-PstI fragment, which corresponds to the first intron of the MYC
gene. Interestingly, and similar to the pattern found in case
1, both the 5' first exon probe and the first exon probe failed
to demonstrate rearrangements in any digest, suggesting
that an unknown stretch of genetic material located 5' to
the breakpoint was deleted in association with the translocation event.
Immunophenotypic analysis showed expression of IgMK;
immunodetectable Tdt was absent.
DISCUSSION
We have identified MYC rearrangements in 3 of 38 (8%)
transformed follicular lymphomas. None of the 18 available
pretransformation biopsies from the corresponding cases
demonstrated a rearranged MYC gene, including two of the
three cases that acquired a MYC rearrangement at histologic progression. Only 1 of 58 control low-grade follicular
lymphomas (case 4) demonstrated rearrangement of the
MYC oncogene, and this case proved to be unusually
aggressive, resulting in the death of the patient 20 months
later. These data support the concept that rearrangements
involving the MYC oncogene are associated with clinically
aggressive disease and are generally acquired at the time of
histologic transformation in a small proportion of follicular
lymphomas that undergo progression.
The incidence of MYC rearrangement that we report in
our progressed follicular lymphomas may underestimate
the total contribution of the MYC gene to the transformation process. Our analysis assumes that MYC involvement
in the high-grade progressed lymphomas will follow the
same rules that have been delineated for the prototypic
Burkitt's lymphoma, where deregulation of the MYC gene is
believed to occur primarily through the uncoupling of the
MYC gene from its 5' regulatory elements or through
mutation of regulatory sites in the first exon (PvuII site and
surrounding sequences). A recent studyz2raises the possibility that in other types of lymphomas other additional
mechanisms of activation may also be important. These
investigators studied MYC involvement in cases of large cell
lymphomas with known 8q24 abnormalities. If one eliminates from consideration their cases of acquired immunodeficiency syndrome (AIDS)-associated lymphomas, they
were able to identify MYC rearrangements in two of eight
cases. Of the remaining six (which presumably had breakpoints far 5' or 3' to the MYC gene), PvuII site mutations
were present in only one additional case. Thus, of the eight
cases with cytogenetic evidence of 8q24 abnormalities, five
(62%) showed none of the usual molecular abnormalities of
the MYC gene that have been previously associated with
deregulation of the oncogene in the Burkitt's lymphomas.
These data raise the possibility that alternative mechanisms
Fig 2. Southern blot analysis of four MYC rearranged cases. Loci depicted are BCL-2, the immunoglobulin heavy chain joining region, and MYC.
Solid lines represent germline restriction fragments; open and closed arrows denote noncomigrating and comigrating rearranged restriction
fragments, respectively. (A) Southern blot analysis of case 1, Hindlll digest probed with BCL-2 mbr, JH, and MYC third exon probes. One JH
rearrangement, common to both pretransformation(F) and transformed (T) lymphoma biopsies, shows comigration with identical BCL-2 mbr
fragments. (Faint bands in the pretransformationfollicular lymphoma are due to the small number of tumor cells in this specimen.) A MYC
rearrangement is detected in the transformed lymphoma, but not in the antecedent follicular lymphoma. (6)Southern blot analysis of case 2,
Hindlll digest probed with BCL-2 mcr. JH, and 5' first exon MYC probes. One JH rearrangement, common to both pretransformation (F) and
transformed IT) lymphoma biopsies, shows comigration with identical BCL-2 mcr fragments. A MYC rearrangement is identified in the
transformed lymphoma, but not in the antecedent follicular lymphoma. (A 5' first exon probe was used to better demonstrate the MYC
rearrangementin this case.) ( C )Southern blot analysis of case 3, Hindlll digest probed with BCL-2 mbr, JH, and MYC third exon probes. Only the
transformed lymphoma (T) was available for study. One JH restriction fragment shows comigration with a BCL-2 mbr rearrangedfragment. A
rearrangedMYC fragment is also present. (D) Southern blot analysis of case 4, EcoRl digest probed with BCL-2 mcr. JH, and MYC third exon
probes. This case was a clinically aggressivefollicular lymphoma (F*) (see text for more detailed discussion). Rearrangements of both BCL-2 mcr
and MYC are present. Neither show comigration with JH.
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
764
of deregulation exist and/or that A d 1 site mutations are
not associated in high frequency with far 5' or 3' rearrangements in lymphomas other than Burkitt's, leaving this class
of rearrangements undercounted in our results. Unfortunately, we do not have cytogenetic data for correlation with
our molecular data.
The pattern of MYC involvement in our progressed
lymphomas is of interest. Each case was unique, and three
of the four displayed some unusual features different from
the ordinary recurring patterns that occur in Burkitt's
lymphomas.
In case 1, the translocation appears to have occurred in
or just 5' to the joining region of the functionally rearranged allele. This would explain our inability to detect
surface Ig in the progressed lymphoma. Although we are
not aware of a similar case of MYC translocating 5' to or
within a productively rearranged Ig gene, replacement of a
rearranged VH region with another has been demonstrated
experimentally,57~58
and there is one report of a Line-1
element inserting itself into the JH segment of a productively rearranged Ig
In both of the above settings,
residual or persistent recombinase activity was implicated
by sequence analysis and this is a likely mechanism in our
case as well.
Cases 3 and 4 failed to demonstrate rearrangement of
MYC into any of the Ig loci, including both light chains.
Although these studies do not eliminate the possibility of
rearrangement into an unidentified Ig locus, they raise the
interesting prospect of a non-Ig locus being involved in the
rearrangement. Several cases have been reported of 3'
rearrangements involvingMYC and T-cell receptor loci.60,61
Although most of these have occurred in T-cell lymphomas
or leukemias, there is one report of this occurrence in a
B-cell lymph0ma.3~MYC rearrangement to a locus that has
been named BCL-3 on chromosome 17q22 has also reported in a case of aggressive prolymphocytic leukemia.39
Both case 3 and 4 were examined for involvement of the
BCL-3 locus. However, neither case displayed comigrations
with the rearranged MYC fragment (data not shown).
Although cases 1 and 4 had breakpoints in the first exon
or intron of the MYC gene, typical sites for the majority of
sporadic Burkitt's lymphomas, both of these cases showed
deletion of an unknown amount of genetic material immediately 5' to the breakpoint. This is distinctly unusual in the
Burkitt's lymphomas, where the translocations involving
the MYC gene are typically reciprocal, and suggests that the
mechanism of translocation in these cases may be more
complex. Thus, three of the four cases had some unusual
features, suggesting that the rearrangement process in
these cases might be different from that which occurs in the
sporadic Burkitt's lymphomas.
Case 4 was the single low-grade follicular lymphoma in
which we identified a MYC rearrangement. Despite the fact
that this case behaved aggressively, it was somewhat surprising that a rearranged, truncated, and presumably deregulated MYC gene was found in a histologically low-grade
follicular lymphoma. We know of only a single additional
case in which a rearranged, truncated MYC gene has been
reported in a low-grade follicular lymphoma.u No clinical
YANO ET AL
follow-up data were reported for that patient. Until recently, even cytogenetic evidence that might implicate
MYC, ie, the presence of 8q24 involvement, in low-grade
follicular lymphomas has been limited to rare
Furthermore, with one e ~ c e p t i o n ?all
~ of the lymphoid
neoplasms reported to contain both the t(14;18) translocation and a translocation involving 8q24 have been aggressive lymphoid leukemias or l y m p h o m a ~ . 2 However,
~~~~~~-~~
as part of a large series, Offit et a1 recently reported
t(8;14)(q24;q32) translocation in 7 of 86 (8.1%) low-grade
lymphomas (defined to include both follicular and small
lymphocytic
It was not stated whether these
cases also possessed the t( 1+18) translocation. Median
follow-up data of 14.6 months were available for five of the
patients, and all were alive without apparent evidence of
disease progression. This is still a relatively short follow-up
period, and it will be extremely interesting to see if these
lymphomas behave more aggressively over time. Others
have reported rare or no cases of t(8q24) involvement in
their series of follicular lymphomas. Notably, in two large
series with a combined total of 111follicular lymphomas, no
cases with 8q24 involvement were observed, although both
groups reported other abnormalities of chromosome 8
(trisomy and duplication 8q).12J4In our series, we were able
to detect MYC alterations in only one of the 76 (1%)
low-grade follicular lymphomas studied (case 4). Because
we do not have cytogenetic correlation, it is possible that
there exists a class of translocations which breaks far 5' or
3' to the MYC gene locus and which is not associated with
the mutations in the first exon. If these kinds of translocations occur with any frequency in low-grade follicular
lymphomas, we would not expect them to be associated with
deregulation of the MYC gene based on the biologic
behavior of these lymphomas.
Despite suggestion^^^ that the MYC gene may play an
important role in histologic progression of low-grade lymphomas, there have been few studies designed to test this
hypothesis directly. The clinical evidence supporting this
proposition has been limited to scattered case reports. De
Jong et alD reported a composite lymphoma in which they
showed that the high-grade lymphoblastic component contained both a BCL-2 and MYC rearrangement, while the
clonally related low-grade follicular lymphoma component
contained only the BCL-2 rearrangement. Lee et aP1
reported a case of small noncleaved cell lymphoma that
evolved from a follicular lymphoma. The follicular lymphoma showed only a BCL-2 rearrangement, while the
clonally related small noncleaved cell lymphoma displayed
rearrangements of both BCL-2 and MYC. Gauwerky et aI3O
reported MYC and BCL-2 involvement in a B-cell lymphoblastic leukemia (B-ALL) from a patient who had had a
5-year history of follicular lymphoma and progressed to
diffuse large cell lymphoma and finally to B-ALL. BritoBabapulle et aP3 reported an additional case of B-ALL that
showed both BCL-2 and MYC rearrangements. This case
was thought to have evolved from a follicular lymphoma
due to the presence of small cleaved cells in the bone
marrow. TheMYC gene in the absence of BCL-2 rearrangement has also been implicated in progression in one case of
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
765
MYC REARRANGEMENTSIN PROGRESSED LYMPHOMAS
an immature Tdt-positive phenotype and without a clear
“blastic transformation” of a chronic lymphocytic leukehistory of a preceding follicular lymphoma. Cases that have
mia.37 Additional cases with coexistent BCL-2 and MYC
had well-documented histories of antecedent follicular
abnormalities have been reported in four high-grade lymlymphoma seem to be able to differentiate (or dedifferenphomas,65,66in several cases of de novo B-ALL,25y34and in
tiate) along two pathways. Some have displayed lymphoblasan aggressiveprolymphocyticle~kemia.3~
However, none of
tic morphology and an immature phenotype as indicated by
these latter cases were reported to have a history of
the presence of Tdt, similar to the de novo B-ALLs with
antecedent low-grade follicular lymphoma, suggesting that
double translocations/rearrangements. Others, like the
MYC may not act as a progression gene in all cases with
double rearrangements.
cases we have reported, have progressed to a phenotypically
mature, Tdt-negative, intermediate- or high-grade lymThere are surprisingly few well-documented cases of
phoma.
transformed follicular lymphomas that have cytogenetics
reported. Of four large series totaling more than 600 cases,
It was of interest to study our 38 progressed lymphomas
for evidence of EBV infection for several reasons. First,
there were only 13 cases of aggressive lymphoma that had a
clear history of an antecedent follicular l y m p h ~ m a . ~ ~ JEBV
~ . ~is~associated
~~
with a considerable fraction of intermediate- and high-grade lymphomas. Second, EBV has been
None of those cases were reported to have an 8q24
shown to upregulate the follicular lymphoma-associated
abnormality. On the other hand, double translocations
protooncogene, BCL-2.56 Nevertheless, none of the 37
involving 18q21 and 8q24 have been reported in several
cases examined contained EBV sequences, eliminating this
cases of intermediate- and high-grade lymphoma/leukeagent from having an important role in the transformation
mias. Although many of these appear to be de novo
process.
B-ALLs,Z,*8there have been a few cases that evolved from
All 18 pretransformation tumors with matched biopsies
an antecedent follicular lymphoma. Thangevelu et aP2
had at least one Ig gene and BCL-2 gene rearrangement in
reviewed the University of Chicago series and identified six
common between the two biopsies. Thus, it is apparent that
high-grade lymphoid leukemias or lymphomas with translomost transformed lymphomas do not represent new second
cations involving both 8q24 and 18q21. Two of the six had a
tumors, but rather are derived from the original follicular
history of follicular lymphoma. Three additional patients
lymphoma clone. This is consistent with the notion that
with B-ALL and an antecedent history of hllicular lymfollicular lymphoma is an acquired, slowly evolving disease
phoma were recently reported by Fiedler et al.35
that, over time, accumulates additional molecular lesions
Thus, the molecular genetic literature and, to a lesser
that drive the low-grade neoplasm to transformation. It
extent, the cytogeneticliterature have implicatedMYC as a
remains to be determined what additional molecular loci,
candidate gene for driving the transformation process.
other than MYC, will be implicated in the majority of
However, because of the small number of progressed cases
follicular lymphomas that undergo histologic progression.
examined and the design of earlier studies, it had not been
possible to estimate the relative importance and frequency
of MYC involvement in histologic transformation. The
ACKNOWLEDGMENT
current study suggests that the MYC gene is involved in a
The authors are grateful to K. Condron and C. Harris for their
small fraction of progressed follicular lymphomas ( 10%).
technical assistance, and to Drs F. Wong-Staal, D. Levens, S.
As discussed, some of the previously reported double
Korsmeyer, M. Cleary, Y. Tsujimoto, N. Raab-Traub, P. Leder, K.
translocation or double rearrangement-bearing tumors
Kelly, and C. Gauwerky for providing DNA probes used in the
study.
generally presented as acute lymphoblastic leukemias with
-
REFERENCES
7. Oviatt DL, Cousar JB, Collins RD, Flexner JM, Stein RS:
Malignant lymphomas of follicular center cell origin in humans. V.
Incidence, clinical features and prognostic implications of transformation of small cleaved cell nodular lymphoma. Cancer 53:1109,
1984
8. Weiss LM, Warnke RA, Sklar J, Cleary M L Molecular
analysis of the t(14;18) chromosomal translocation in malignant
lymphomas. N Engl J Med 317:1185,1987
9. Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW,
Epstein AL,Korsmeyer SJ: Cloning the chromosomal breakpoint
of t(14;18) human lymphomas: Clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41:899,1985
10. Cleary ML, Smith SD, Sklar J: Cloning and structural
analysis of cDNAs for bcZ-2 and a hybrid bcl-2/immunoglobulin
transcript resulting from the t( 1 4 3 ) translocation. Cell 4719,
1986
11. Hockenbery D, Nunez G, Milliman C, Schreiber RD,
Korsmeyer S J BcZ-2 is an inner mitochondrial membrane protein
that blocks programmed cell death. Nature 348:334,1990
12. Yunis JJ, Frizzera G, Oken MM, McKenna J, Theologides
1. Risdall R, Hoppe RT, Warnke R: Non-Hodgkin’slymphoma.
A study of the evolution of the disease based upon 92 autopsied
cases. Cancer 44529,1979
2. Cullen MH, Lister TA, Brearley RL, Shand WS, Stansfeld
AG: Histological transformation of non-Hodgkin’s lymphoma. A
prospective study. Cancer 44:645,1979
3. Ersboll J, Schultz HB, Pedersen-BjergaardJ, Nissen NI: Follicular low-grade non-Hodgkin’s lymphoma: Long term outcome
with or without tumor progression. Eur J Haematol42:155,1989
4. Garvin AJ, Simon RM, Osborne CK, Merrill J, Young RC,
Berard CW: An autopsy study of histologic progression in nonHodgkin’s lymphomas: 192 cases from the National Cancer Institute. Cancer 52393,1983
5. Hubbard SM,Chabner BA, DeVita VT,Jr, Simon R, Berard
CW, Jones RB, Garvin AJ, Canellos GP, Osbome CK, Young R C
Histologic progression in non-Hodglun’slymphoma. Blood 59:258,
1982
6. Acker B, Hoppe RT, Colby TV, Cox RS, Kaplan HS,
Rosenberg SA: Histologicconversionin the non-Hodgkin’slymphomas. J Clin Oncol1:11,1983
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
766
A, Arnesen M: Multiple recurrent genomic defects in follicular
lymphoma. A possible model for cancer. N Engl J Med 31 6:79,
1987
13. Richardson ME, Quanguang C, Filippa DA, Offit K, Hampton A, Koduru PRK, Jhanwar SC, Lieberman PH, Clarkson BD,
Chaganti RSK Intermediate- to high-grade histology of lymphomas carrying t(14;18) is associated with additional nonrandom
chromosome changes. Blood 70444,1987
14. Armitage JO, Sanger WG, Weisenburger DD, Harrington
DS, Linder J, Bierman PJ, Vose JM, Purtilo DT: Correlation of
secondary cytogenetic abnormalities with histologic appearance in
non-Hodgkin’s lymphomas bearing t( 14;18)(q3&q21). JNCI 80:
576,1988
15. Levine EG, Juneja S, Arthur D, Garson OM, Machnicki JL,
Frizzera G, Ironside P, Cooper I, Hurd DD, Peterson BA, Mosel
D, Bloomfield CD: Sequential karyotypes in non-Hodgkin’s lymphoma: Their nature and significance. Genes Chrom Cancer 1:270,
1990
16. Stewart TA, Bellve AR, Leder P: Transcription and promoter usage of the myc gene in normal somatic and spermatogenic
cells. Science 226:707,1984
17. Pfeifer-Ohlsson S, Goustin AS, Rydnert J, Wahlstrom T,
Bjersing L, Stehelin D, Ohlsson R: Spatial and temporal pattern of
cellular myc oncogene expression in developing human placenta:
Implications for embryonic cell proliferation. Cell 3835,1984
18. Vaux DL, Cory S, Adams J M Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B
cells. Nature 335:440,1988
19. Strasser A, Harris AW, Bath ML, Cory S: Novel primitive
lymphoid tumors induced in transgenic mice by cooperation
between myc and bcl-2. Nature 348:331,1990
20. McDonnell TJ, Korsmeyer SJ: Progression from lymphoid
hyperplasia to high grade malignant lymphoma in mice transgenic
for the t(14;18). Nature 349:254,1991
21. Chenevix-Trench G, Behm FG, Westin EH: Somatic rearrangement of the c-myc oncogene in primary human diffuse
large-cell lymphoma. Int J Cancer 38513,1986
22. Ladanyi M, Offit K, Jhanwar SC, Filippa DA, Chaganti
RSK MYC rearrangement and translocations involving band 8q24
in diffuse large cell lymphomas. Blood 77:1057,1991
23. Nagai M, Ikeda K, Tasaka T, Irino S: Genomic rearrangement of the c-myc proto oncogene in non-AIDS-related lymphoma
in Japan. Leukemia 5:462,1991
24. Scarpa A, Borgato L, Chilosi M, Capelli P, Menestrina F,
Bonetti F, Zamboni G, Pizzolo G, Hirohashi S, Fiore-Donati L
Evidence of c-myc gene abnormalities in mediastinal large B-cell
lymphoma of young adult age. Blood 78:780,1991
25. Mufti GJ, Hamblin TJ, Oscier DG, Johnson S: Common
ALL with pre-B-cell features showing (8;14) and (14;18) chromosome translocations. Blood 62:114,1983
26. Pegoraro L, Palumbo A, Erikson J, Falda M, Giovanazzo B,
Emanuel BS, Rovera G, Nowell PC, Croce CM: A 14;18 and an
8;14 chromosome translocation in a cell line derived from an acute
B-cell leukemia. Proc Natl Acad Sci USA 81:7166,1984
27. Geisler C, Philip P, Plesner T, Anderson P, Zeuthen J,
Guldhammer B, Hansen MM: Simultaneous presence of translocations t(14;18) and t(28) in a case of chronic lymphocytic leukemia.
Cancer Genet Cytogenet 2235,1986
28. Gluck WL, Bigner SH, Borowitz MJ, Brenckman WD Jr:
Acute lymphoblastic leukemia of Burkitt’s type (L3 ALL) with 8;22
and 14;18 translocations and absent surface immunoglobulins. Am
J Clin Pathol85:636,1986
29. de Jong D, Voetdijk BMH, Beverstock GC, van Ommen
GJB, Willemze R, Kluin PM: Activation of the c-myc oncogene in a
YANO ET AL
precursor-B-cell blast crisis of follicular lymphoma, presenting as
composite lymphoma. N Engl J Med 318:1373,1988
30. Gauwerky CE, Haluska FG, Tsujimoto Y, Nowell PC, Croce
CM: Evolution of B-cell malignancy: Pre-B-cell leukemia resulting
from MYC activation in a B-cell neoplasm with a rearranged BCL-2
gene. Proc Natl Acad Sci USA 85:8548,1988
31. Lee JT, Innes DJ, Williams M E Sequential bcl-2 and c-myc
oncogene rearrangements associated with the clinical transformation of nomHodgkin’s lymphoma. J Clin Invest 84:1454,1989
32. Thangavelu M, Olopade 0, Beckman E, Vardiman JW,
Larson RA, McKeithan TW,Le Beau MM, Rowley JD: Clinical,
morphologic, and cytogenetic characteristics of patients with lymphoid malignancies characterized by both t(14;18)(q32;q21) and
t(8;14)(q24;q32) or t(8;22)(q24;qll). Genes Chrom Cancer 2:147,
1990
33. Brito-Babapulle V, Crawford A, Khokhar T, Laffan M,
Matutes E, Fairhead S, Catovsky D: Translocations t( 14;18) and
t(8;14) with rearranged bcl-2 and c-myc in a case presenting as
BALL (W). Leukemia 5233,1991
34. Kramer MHH, Raghoebier S, Beverstock GC, de Jong D,
Kluin PM, Kluin-Nelemans J C De novo acute B-cell leukemia
with translocation t(14;18): An entity with a poor prognosis.
Leukemia 5:473,1991
35. Fiedler W, Weh HJ, Zeller W, Fonatsch C, Hillion J, Larsen
C, Wormann B, Hossfeld DK: Translocation (14;18) and (8;22) in
three patients with acute leukemia/lymphoma following centrocytid
centroblastic non-Hodgkin’s lymphoma. Ann Hematol 63:282,
1991
36. The Fifth International Workshop on Chromosomes in
Leukemia-Lymphoma: Correlation of chromosome abnormalities
with histologic and immunologic characteristics in non-Hodgkin’s
lymphoma and adult T cell leukemia-lymphoma. Blood 701554,
1987
37. Rimokh R, Rouault J-P, Wahbi K, Gadoux M, Lafage M,
Archimbaud E, Charrin C, Gentilhomme 0, Germain D, Samarut
J, Magaud J-P: A chromosome 12 coding region is juxtaposed to
the MYC proto-oncogene locus in a t(8;12)(q24;q22) translocation
in a case of B-cell chronic lymphocytic leukemia. Gen Chrom
Cancer 3:24,1991
38. Park JK, McKeithan TW,Le Beau MM, Bitter MA, Franklin
WA, Rowley JD, Diaz MO: An (8;14)(q24;qll) translocation
involving the T-cell receptor a-chain gene and the MYC oncogene
3’ region in a B-cell lymphoma. Gen Chrom Cancer 1:15,1989
39. Gauwerky CE, Huebner K, Isobe M, Nowell PC, Croce CM:
Activation of MYC in a masked t(8;17) translocation results in an
aggressive B-cell leukemia. Proc Natl Acad Sci USA 8623867, 1989
40. The Non-Hodgkin’s Lymphoma Pathologic Classification
Project: National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas. Cancer 49:2112, 1982
41. Cossman J, Neckers LM, Hsu SM, Longo D, Jaffe ES:
Low-grade lymphomas. Expression of developmentally regulated
B-cell antigens. Am J Pathol 115:117,1984
42. Braziel RM, Keneklis T, Donlon JA, Hsu S-M, Cossman J,
Bollum FJ, Jaffe ES: Terminal deoxynucleotidyl transferase in
non-Hodgkin’s lymphoma. Am J Clin Pathol80:655,1983
43. Raffeld M, Wright JJ, Lipford E, Cossman J, Longo DL,
Bakhshi A, Korsmeyer SJ: Clonal evolution of t(14;18) follicular
lymphomas demonstrated by immunoglobulin genes and the 18q21
major breakpoint region. Cancer Res 47:2537,1987
44. Raab-Traub N, Flynn K The structure of the termini of the
Epstein-Barr virus as a marker of clonal cellular proliferation. Cell
47:883,1986
45. Yano T, van Krieken JHJM, Magrath IT, Longo DL, Jaffe
ES, Raffeld M: Histogenetic correlations between subcategories of
small non-cleaved cell lymphomas. Blood 79:1282,1992
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
MYC REARRANGEMENTSIN PROGRESSED LYMPHOMAS
46. Cesarman E, Dalla-Favera R, Bentley D, Groudine M:
Mutations in the first exon are associated with altered transcription
of c-myc in Burkitt lymphoma. Science 238:1272,1987
47. Szajnert M-F, Saule S, Bornkamm GW, Wajcman H, Lenoir
GM, Kaplan J - C Clustered somatic mutations in and around first
exon of non-rearranged c-myc in Burkitt lymphoma with t(8;22)
translocation. Nucleic Acids Res 15:4553,1987
48. de Jong D, Voetdijk BMH, van Ommen GJB, Kluin P M
Alterations in immunoglobulin genes reveal the origin and evolution of monotypicand bitypic B cell lymphomas. Am J Patholl34:l
233,1989
49. Cleary ML, Galili N, Trela M, Levy R, Sklar J Single cell
origin of bigenotypic and biphenotypic B cell proliferations in
human follicular lymphomas. J Exp Med 167582,1988
50. Comillet P, Rimokh R, Berger F, Ffrench M, Rouault J-P,
Wahbi K, Bryon P-A, Gentilhomme 0, Coiffier B, Germain D,
Magaud J-P: Involvement of the BCL 2 gene in 131 cases of
non-Hodgkin’s B lymphomas: Analysis of correlations with immunological findings and cell cycle. Leuk Lymph 4355,1991
51. Magrath I: The pathogenesis of Burkitt’s lymphoma. Adv
Cancer Res 55:133,1990
52. Subar M, Neri A, Inghirami G, Knowles DM, Dalla-Favera
R Frequent c-myc oncogene activation and infrequent presence of
Epstein-Barr virus genome in AIDS-associated lymphoma. Blood
72667,1988
53. List AF, Greco FA, Vogler LB: Lymphoproliferative diseases in immunocompromised hosts: The role of Epstein-Barr
virus. J Clin Oncol5:1673,1987
54. Cleary ML, Nalesnik MA, Shearer WT, Sklar J: Clonal
analysisof transplant associated lymphoproliferationsbased on the
structure of the genomic termini of the Epstein-Barr virus. Blood
72:349,1988
55. Su I-J, Hsieh H-C, Lin K-H, Uen W-C, Kao C-L, Chen C-J,
Cheng A-L, Kadin ME, Chen J-Y Aggressive peripheral T-cell
lymphomas containing Epstein-Barr viral DNA A clinicopathologic and molecular analysis. Blood 77799,1991
56. Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang
F, Longnecker R, Kieff E, Rickinson A Induction of bcf-2 expression by Epstein-Barr virus latent membrane protein 1protects
infected B cells from programmed cell death. Cell 65:1107,1991
767
57. Kleinfield R, Hardy RR, Tarlinton D, Dangl J, Herzenberg
LA, Weigert M: Recombinationbetween an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a
Lyl+ B-cell lymphoma. Nature 322843,1986
58. Reth M, Gehrmann P, Petrac E, Wiese P: A novel VH to
VHDJH joining mechanism in heavy-chain-negative (null) pre-B
cells results in heavy-chainproduction. Nature 3229340,1986
59. Yancopoulos GD, DePinho RA, Zimmerman KA, Lutzker
SG, Rosenberg N, Alt FW: Secondary genomic rearrangement
events in pre-B cells: VHDJH replacement by a LINE-1 sequence
and directed class switching. EMBO J 53259,1986
60. Mathieu-Mahul D, Caubet JF,Bemheim A, Mauchauffe M,
Palmer E, Berger R, Larsen CT: Molecular cloning of a DNA
fragment from human chromosome 14(14qll) involved in T-cell
malignancies. EMBO J 43427,1985
61. Finver SN, Nishikura K, Finger LR, Haluska FG, Finan J,
Nowell PC, Croce CM: Sequence analysis of the MYC oncogene
involved in the t(8;14)(q24;qll) chromosome translocation in a
human leukemia T-cell line indicates that putative regulatory
regions are not altered. Proc Natl Acad Sci USA 85:3052,1988
62. Juneja S, Lukeis R, Cooper TI, Szelag G, Parkin JD,
Ironside P, Garson OM: Cytogenetic analysis of 147 cases of
non-Hodgkin’s lymphoma: Non-random chromosomal abnormalities and histologicalcorrelations. Br J Haematol76231,1990
63. Donti E, Falina B, Pelicci PG, Donti GV, Rosetti A, Martelli
M, Grignani F: Immunological and molecular studies in a case of
follicular lymphoma with an extra chromosome 12 and t(28)
translocation. Leukemia 241,1988
64. Offit K, Wong J, Filippa DA, Tao Y, Chaganti RSK
Cytogenetic analysis of 434 consecutivelyascertained specimens of
non-Hodgkin’s lymphoma: Clinical correlations. Blood 77: 1 508,
1991
65. Lee M-S, Blick MB, Pathak S, Trujillo JM, Butler JJ, Katz
RL, McLaughlin P, Hagemeister FB, Velasquez WS, Goodacre A,
Cork A, Gutterman JU,Cabanillas F The gene located at
chromosome 18 band 921 is rearranged in uncultured diffuse
lymphomas as well as follicular lymphomas.Blood 70:90,1987
66. Koduru PRK, Offit K Molecular structure of double reciprocal translocations: Significance in B-cell lymphomagenesis. Oncogene 6145,1991
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1992 80: 758-767
MYC rearrangements in histologically progressed follicular
lymphomas
T Yano, ES Jaffe, DL Longo and M Raffeld
Updated information and services can be found at:
http://www.bloodjournal.org/content/80/3/758.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American
Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.