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RAPID COMMUNICATION
LA23 Rearrangements in Non-Hodgkin's Lymphoma: Correlation With
Histology, Immunophenotype, Karyotype, and Clinical Outcome
in 217 Patients
By Christian Bastard, Clotilde Deweindt, Jean Pierre Kerckaert, Bernard Lenormand, Annick Rossi,
Francesco Pezzella, Christophe Fruchart, Christian Duval, Mathieu Monconduit, and Herve Tilly
We have recently shown that an evolutionary conserved
gene LAZ3, encoding a zinc finger protein, is disrupted and
overexpressed in some B-cell lymphomas (mainly with a
large cell
component)
that
show
chromosomal rearrangements involving 3q27. Because the breakpoints involved in these rearrangements are focused in a narrow major translocation cluster (MTC) on chromosome 3, we used
genomic probes from thisregion t o study themolecular rearrangements of LAZ3 in a large series of patients (217) with
non-Hodgkin's lymphoma (NHL). Southern blot analysis
showed LAZ3 rearrangement in 43 patients (19.8%).Rearrangement was found in 11 of the 84 patients (13%) with
follicular lymphoma but was most frequent in aggressive
lymphoma (diffuse mixed, diffuse large cell, and large cell
immunoblastic subtypes), in which 31 of the 114 patients
(27%) were affected. The highest proportion of LAZ3 alteration was observed in B-cell aggressive lymphoma (26 of 71
cases, 37%). Eleven of the 32 patients with 3q27 chromosomal abnormality hadno LAZ3 rearrangement, suggesting
the possibility of LAZ3 involvement outside the MTC. On the
other hand, 18 of the 39 patients with LAZ3 rearrangement
and available cytogenetic results did nothave visible chromosomal break at 3q27, suggesting that almost a half of the
rearrangements are not detectable by cytogenetic methods.
No statistical association could be foundbetween LAZ3 status and initial features of thedisease or clinical outcomein
either follicular oraggressive lymphomas. We conclude that
LAZ3 alteration is a relativelyfrequent
event in B-cell
lymphoma, especially in those of aggressive histology. It
could be used as a genomic marker of the disease, and further studies are needed t o clarify clinical implications of
these alterations.
0 1994 by The American Society of Hematology.
Tissue samples. Fresh lymph nodes were divided for morphoPECIFIC RECURRING chromosomal aberrations have
logic, immunologic, and cytogenetic studies as previously debeen reported in most hematologic malignancies. In Bscribed." Cells were cryopreserved for various periods of time becell neoplasms, several translocations involve the Ig genes
fore DNA extraction. All histologic material was reviewed by the
at bands 14q32,2p12, and 22qll.I The most frequent defects
same pathologist and classified according to the Working Formulain non-Hodgkin's lymphoma (NHL) are the (14; 18) translotion for Clinical Usage."
cation, associated mainly with follicular lymphoma*; the
DNA extraction and Southern blot analysis. DNA was extracted
(8; 14) translocation and its variants found in Burkitt's
by the sarkosyl-proteinase K-phenokhloroform method. After dil y m p h ~ m a ~and
. ~ ; the (1 1 ;14) translocation associated with
gestion with restriction endonucleases, DNA fragments were electrointermediate or "mantle zone" lymphoma.' The molecular
phoresed on 0.8% agarose gels, transferred onto nylon N+ memanalysis of these chromosomal defects has shown that they lead
branes, and hybridized according to the recommendations of the
suppliers (Amersham). DNAs were digested using at least two of
totheoncogenicconversion
of genessuch
as BCL-2,"'
four restriction enzymes (EcoRI, BamHI, HindIII, Xba I). The genoa regulator of apoptotic cell death: or of proto-oncogenes
mic probes F370, F372, and F381 (Fig 1) have been previously
encoding transcription regulators such as MYC'03LLand
described.18
CCND1/PRAD.'2"4
Cytogeneticanalysis. Cells (2 X 10b/mL) were cultured overWe have previously reported that translocations involving
night in RPM1 1640 supplemented with 10% fetal calf serum in the
chromosome 3q27 and Ig gene regions are the third most
presence of colchicine (0.02 pg/mL). Cells were incubated for 25
common specific group of translocations in NHL, and are
associated mainly
with
diffuse large cell lymphoma
(DLCL)." In this subset of NHL, numerous chromosomal
From the Department of Cytogenetics, CentreRkgional de Transdefects are found that affect the same region on chromosome
fusion Sanguine et de Gdnne'tiqueHumaine, Bois Guillaume; INSERM
3 but not the Ig gene locations. We and others have shown
U124, Institut de Recherche sur le Cancer, Lille; the Department of
that most of these rearrangements involve the same major
Biological Hematology and Cellular Immunology, Hbpital Charles
Nicolle, Rouen; the Department of Clinical Hematology, Centre
translocation cluster (MTC) on chromosome 3.'h"8 These
Henri Becquerel, Rouen, France; and the Department of Hematoltranslocations result in the disruption and deregulation of a
ogy, John Radcliffe Hospital, Oxford, UK.
gene, LAZ3,I9 also named BCL-6," encoding a conserved
Submitted January 25, 1994; accepted February 22, 1994.
zinc finger protein that may act as a transcriptional regulator
Supported in part by grants from la Ligue Nationale FranCaise
involved in differentiation and development. To confirm the
Contre le Cancer and la Fondation de France.
prominent role of the LAZ3 gene in the pathogenesis of NHL,
Address reprint requests to Christian Bastard, MD, Centre Re"
weused genomic probes derived from the 3q27MTC to
gional de Transfusion Sanguine, 609 Chemin de la Brett?que, BP
study DNAs from a series of 217 patients with this disease.
58, 76232 Bois Guillaume Cedex, France.
S
MATERIALS AND METHODS
Patients. High molecular weight DNA was obtained from biopsy
specimens of 217 adult patients admitted to the Centre Henri Becquerel (Rouen, France) between September 1984 and April 1993 for
the diagnosis and treatment of NHL.
Blood, Vol 83, No 9 (May l), 1994: pp 2423-2427
The publication costsof this article were defrayedin part by page
chargepayment. This article must therefore be hereby marked
"adveaisement" in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1994 by The American Society of Hematology.
0006-4971/94/8309-07$3.00/0
2423
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2424
BASTARD ET AL
1OKB
0
l
MTC
minutes at 37°C in 0.075 m o m potassium chloride, fixed in methanol-acetic acid (3: l), and spread on clean, dry slides. R-banding was
obtained according toSehested?’ and karyotypes were described
according to the International System for Human Cytogenetic Nomenclature.*’
Correlation with clinical presentation and outcome. For this retrospective study, we only considered patients who had a tumor sample studied at the time of primary diagnosis. Two patient populations
were selected: patients with follicular lymphomas and patients with
aggressive lymphomas as defined by the International Non-Hodgkin’s Lymphoma Prognostic Factor Proje~t,’~
namely diffuse mixed,
diffuse large cell, and large cell immunoblastic subtypes. For each
population, the association between LAW rearrangement and clinical
features was studied. The clinical features studied were: age, sex,
performance status, presence of B symptoms, Ann Arbor stage, bone
marrow involvement, number of extranodal sites, presence of a mass
greater than 10 cm, LDH level, serum albumin level, and overall
survival. For aggressive lymphoma only, association with the International Prognostic Index,” response to treatment, and disease-free
survival were also examined.
Statistical methods. Associations between LA23 rearrangement
and initial clinical features were analyzed with the two-sided chisquared test. Survival curves were plotted using the method of
Kaplan and Meief’ and were compared by the log-rank test.26Analyses were performed with use of JPSI statistical software (developed
by P. Kwiatkowski, Centre Jean Perrin, Clermont-Ferrand, France).
RESULTS
Fig 1. Partial map of the 3q27
rqion. Shadedboxesindicate
tho locationof W e x o n r . MTC,
2
3
4 5 6 7 0
9
major
trandocatlon
cluster.
Genomicprobes F370, F372,and
F381 are indicated
by
black
boxes. Restriction enzymes symbol are: E, € d l ; B, & d l ; X,
Xba I; Xh, Xbo 1.
patients with aggressive B-cell lymphoma, the LAZ3 gene
was involved in 26patients (37%), mainly with diffuse large
cell (14/46) and immunoblastic(6/12) lymphomas. Onlyone
patient with T-cell lymphoma was found to have an LAZ3
rearrangement. In thiscase, the results of morphologic evaluation and immunostaining were confirmed by the absence
ofIg gene rearrangement and the presence of a C@ rearrangement. The only anaplastic large cell lymphoma of
B-cell phenotype included in this study had
an M 3 rearrangement, whereas four T-anaplastic large cell lymphomas appeared to be unaffected.
Good quality metaphases were obtained in 201 patients,
32 of which had adetectable abnormality of the 3q27 region
(16%) (Table 3). LAZ3 rearrangement was found in 14 of
the18 patients with translocations involving3q27andIg
genes regions.Amongthe14
patients withchromosomal
3q27 defects (12 translocations, 2 deletions) that did not
affect Ig gene regions, 7 showed LAB rearrangements, as
did 18 patients with no evident cytogenetic involvement of
the 3q27 region. Thirteen of these had a complex karyotype,
whereas 5 displayed a more simple pattern: 47,xyy; 46,xx,
t(2; 18)(p12;q21); 46,xx, t(14; 18)(q32;q21); 47,xy, +5;
46,xx, t( 15;2O)(q22;ql3)/46,xx,der(9)(~24).
LAZ3 rearrangement was found to be associated, atthe
cytogenetic level, with other specific abnormalities in 12 of
39 patients. These translocations were a t ( 14; 18) or a t(2; 18)
LAZ3 rearrangements were detected in 43 of the 217 samples (19.8%). A common HindIII polymorphism was also
noted in 15 patients. All histologic subtypes of the Working
Table 1. Incidence of LAM Rearrangement
Formulation were represented in thepatient population (TaAmong 217 Cases of NHL
ble l ) and the involvement of LA23 was observed in all of
Cases With L9z3 Rearrangement/
them, withthe exception of lymphocytic, lymphoblastic, and
Total Cases Studied
Histology
diffuse small noncleaved cell lymphomas.
Lymphocytic
014
Eleven of the 84 follicular lymphomas (13%) were found
Follicular
to be rearranged. M 3 alterations appeared
to be more frecells
Small
3/38
quent in large cell follicular lymphoma (4/10) than in small
cells
largeandsmall
Mixed,
4/36
or mixed cell follicular lymphoma (7174). However,
most of
cells
Large
4110
LAZ3 rearrangements were
observed
in aggressive
Diffuse
lymphoma (diffuse mixed, diffuse large cell,
and large
cell
cells
cleaved
Small
115
cells
largeand
small
Mixed,
5/24
immunoblastic), affecting 31 of the 114 patientsin these
cells
Large
14/51
subtypes (27%).
lmmunoblastic
9/29
Immunophenotype could be determined in 204 tumors,
Unclassifiable
3110
which comprised 163 B-cell and 41 T-cell lymphomas. Of
Lymphoblastic
016
the 163 B-cell lymphomas (including follicular lymphomas),
noncleaved
cells
small
Diffuse
014
38 were rearranged (Table 2).
Within the subgroup of 71
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2425
LAZ3 REARRANGEMENTS IN NHL
Table 2. Incidence of LAZ3 Rearrangemant
Among 163 Cases of B-Cell NHL
Cases With W 3
RearrangemenKases Studied
Histology
Lymphocytic
Follicular
Small cells
Mixed, small and large cells
Large cells
Diffuse
Small cleaved cells
Mixed, small and large cells
Large cells
lrnmunoblastic
Unclassifiable
Diffuse small noncleaved cells
Table 4. Correlations Between Main Clinical Characteristics and
Presence or Absence of LAZ3 Rearrangement inthe 83 Patients
W t h Aggressive Lymphoma Studied atthe Time of Diagnosis
013
All patients
3/35
4/35
4110
115
3/9
14/46
6112
314
014
in 8 cases, a t(8; 14) or a t(8;22) in 2 cases, and the association of a t(8; 14) and a t(14; 18) in 2 cases.
The association of LAU rearrangement with clinical features could be studied in 55 patients with follicular
lymphoma and in 83 patients with aggressive lymphoma
(Table 4) examined at the time of diagnosis, but no statistical
correlations were observed in either subgroup. LAZj rearrangement did not influence survival in patients with follicular lymphoma (Fig 2). The overall survival of patients with
aggressive lymphoma and an LAU rearrangement appeared
slightly better than those of patients without rearrangement,
but the difference was not significant (P > .55) (Fig 3).
DISCUSSION
Molecular studies of the t(14; 18) and of the t(8; 14) have
greatly improved our understanding of the pathogenesis of
follicular and Burkitt's lymphoma. However, very little is
known about the genes involved in DLCL, the most frequent
subtype of lymphoma."
We have previously shown that translocations involving
Table 3. Incidence of LAZ3 Rearrangement in 32 Cases of NHL With
Chromosomal Abnormalityat Band 3q27
Cases With W 3
Partial Karyotype
RearrangernenUCases Studied
t(3;14)(q27;q32)
t(3;22)(q27;qlI)
t(2;3)(p12:q27)
t(2:3)(q22;q27)
t(3;4)(q27;pl1)
t(3;6)(q27;p21)
t(3;6)(q27;q15)
t(3;7)(q27;p12)
t(3;8)(q27;q24)
t(3;15)(q27;q21)
der(3)t(3;?)(q27;7)*
del(3)(q27)
All
12114
112
112
011
112
111
011
111
111
1I2
113
112
21/32
* t(3;?) denotes a translocation with unidentified chromosomal
material.
Age
s 6 0 yrs
>60 yrs
Sex
M
F
Performance status
0-1
2-4
B symptoms
No
Yes
Ann Arbor stage
1-11
Ill-IV
Bone marrow involvement
No
Yes
Number of extranodal sites
0-1
22
Largest mass
< l 0 cm
210 cm
Serum albumin level*
S35 g/L
>35 glL
Serum LDH level*
SN
>N
International Index (24)*
0-1 Risk factor
2-3 Risk factors
4-5 Risk factors
LA13
LAZ3 Not
Rearranged
Rearranged
25
58
14
11
34
24
>.5
18
7
35
23
>.3
20
5
40
18
>.3
16
9
29
29
>.2
13
12
19
39
>.05
20
5
40
18
>.3
21
4
37
21
>.l
14
11
36
22
>.5
8
25
31
>.2
17
8
13
15
38
>.3
11
7
3
14
26
13
>.l
PValue
Some patients had missing data for serum albumin and LDH levels.
the 3q27 region and Ig genes locations were frequently observed in NHL, mainly of large cell type.I5 Breakpoints on
chromosome 3 are clustered into an MTC of 4 kb, together
with those of several chromosome rearrangements of the
same 3q27 region that do not affect Ig genes as partner."
We have cloned a gene, L A Z 3 , encoding an evolutionary
conserved zinc finger protein, that is disrupted and abnormally overexpressed in patients with3q27 molecular rearrangements, and postulated that the deregulation of this
transcription factor (of unknown function) could be an important event in the pathogenesis of large cell lymphoma."
The same breakpoint ~ l u s t e r ' ~and
. ' ~ the same genez0have
been cloned by others and named BCL-6.
To assess the frequency and the significance of LA23
rearrangements, we studied a series of 2 17 patients and found
that the 3q27 region was affected in 13% of follicular
lymphomas and 27% of DLCL. M 3 rearrangements appeared to be nearly restricted to B-cell lymphoma because
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2426
BASTARD ET AL
only 1 of 39 immunologically characterized positive samples
was of T-cell phenotype. In the group of aggressive
lymphoma of B-cell phenotype, the overall frequency of
LAZ3 rearrangements reaches 37%, in accordance with the
results reported by Ye et al.”
As suspected from the cytogenetic analy~is,’~
LAZ3 rearrangement was found in a proportion of follicular
lymphoma cases (13%). These results differs from those of
Ye et a1’: who did not observe any BCL-6 alteration in a
series of 28 patients with follicular lymphoma. The fact that
LAZ3 rearrangement could be observed in some patients with
follicular lymphoma at the time of diagnosis, and that it did
not appear to influence survival, suggests that LAZ3 is not
associated with clinical progression or histologic transformation.
Correlation with cytogenetic data showed that 1 1 of the
32 patients displaying a chromosomal defect of the 3q27
region had no LAZ3 rearrangement. In these cases, the defect
could either affect another gene or, more likely, affect the
LAZ3 gene at a breakpoint located outside the MTC. Thus,
the reported frequency of LAZ3 involvement could represent
an underestimation of the real frequency. On the other hand,
18 of the 39 patients with LAZ3 rearrangement and available
cytogenetic results did not exhibit visible chromosomal
break of the 3q27 region. This result suggests that almost
50% of LAZ3 rearrangements may be invisible by cytogenetic methods.
We were unable, in this series, to show any correlation
between clinical characteristics and LAW rearrangement.
Recently, Offit et alZ8described an association between BCL6 rearrangement and a subset of DLCL with high proportion
of extranodal disease who enjoy a favorable outcome. Our
study did not support this association. As both studies were
retrospective, inclusion criteria might have been different.
Our study included only patients with available cytogenetic
data, and this fact probably discarded some patients with
only extranodal localization at the time of diagnosis.
In conclusion, this study confirms the importance of alterations of LAZ3 in NHL, involving a third of the patients
with aggressive B-cell lymphoma. Further studies are now
required to understand the mechanism of action of this new
oncogene, and to define whether or not its alterations have
”..
U)
C
.-
.B
S
v)
c
U
g
n
OS8l
0.6
0.2-
0
-m+-mI
0
I
1 2 2 4 3 6 4 8 6 0 7 2 8 4
Months
Fig 2. Survivalof the 55 patients with follicularlymphomaaccording to the presence (n = 8) or the absence In = 47) of LAZ3
rearrangement at diagnosis ( P = .96).
1 1
.-P
.z
5
v)
0.2
0
1 2 2 4 3 6 4 8 6 0 7 2 8 4
Months
Fig 3. Survival of the 83 patients with aggressive lymphoma according to the premnce (n = 251 or the absence of LAM (n = 5 8 )
rearrangement at diagnosis (P = 551.
any prognostic significance in NHL. This genomic marker,
allowing the identification and follow-up of a homogeneous
group of patients, will probably represent an important new
approach to the diagnosis and management of patients with
B-cell lymphoma. We are currently developing a polymerase
chain reaction assay to assess minimal residual disease in
patients with a t(3; 14) translocation.
ACKNOWLEDGMENT
We are grateful to Dr David Y. Mason for his critical reading of
the manuscript.
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LAZ3 REARRANGEMENTS IN NHL
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1994 83: 2423-2427
LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with
histology, immunophenotype, karyotype, and clinical outcome in 217
patients
C Bastard, C Deweindt, JP Kerckaert, B Lenormand, A Rossi, F Pezzella, C Fruchart, C Duval, M
Monconduit and H Tilly
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