(CANCER RESEARCH 49, 1275-1281, March 1. 1989]
Nonrandom Rearrangement of Chromosome 14 at Band q32.33 in Human
Lymphoid Malignancies with Mature B-Cell Phenotype1
Kazuhiro Nishida,2 Masafumi Taniwaki, Shinichi Misawa, and Tatsuo Abe
Third Department of Medicine (K. M., M. T., S. M] and Department of Hygiene [T. A.], Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku,
Kyoto 602, Japan
ABSTRACT
Chromosomes were studied in 61 patients with differentiated B-cell
malignancies including 21 with non-Hodgkin's lymphoma (NHL), three
with hairy cell leukemia (HCL), eight with Waldenstrom's macroglobulinemia (YVM),and 29 with plasma cell disorder. Chromosomally abnor
mal clones were identified in 35 of 61 patients studied: all with NHL, all
with HCL, three of eight with WM, and eight of 29 with plasma cell
disorder. The most recurrent chromosomal abnormality, observed in 26
of the 35 patients whose chromosomes were abnormal, was a re
arrangement involving chromosome 14, in which an additional segment
was attached at band 32 in the long arm to form a 14q+ marker
chromosome. This rearrangement was seen in 17 patients with NHL,
three with HCL, one with WM, and five with plasma cell disorder. In
NHL, the rearrangement correlates with histológica!subclasses: t(14;18)
in all four patients with malignant lymphoma (MI Hollimlar. mixed
small cleaved and large cell; t(8;14) or its variant form, t(8;22), in all six
with Ml .-small noncleaved cell; and t(ll;14) in two of three with Ml diffuse, mixed small and large cell. A t(14;18) was also found in each
patient with Ml -diffusi-, large cell, WM, and multiple myeloma, and a
variant three-way translocation, t(5;18;14) (ql3;q21;q32), in one with
ML-diffuse, small cleaved cell. The donor sites for these I4q+ were
assigned to oncogene loci: c-mir (8q24), bcl-l (1 Iql3), and hcl-2 (18q21).
Moreover, the donor sites were also located near ¡mmunoglobulinlight
chain gene loci in each patient with leukemic ML-diffuse, mixed small
and large cell, 1(2:1-1) (pl3;q32.3), and HCL, t(14;22Xq32.3;qll.2).
These findings suggest that chimeric DNA formation, not only between
an immunoglobulin gene and a certain oncogene, but also between the
IgH gene and one of the IgL genes may be potentially relevant in
malignant B-cell proliferation.
INTRODUCTION
Cytogenetic studies have disclosed a close association of
specific chromosomal translocations with histológica! classifi
cation in B-cell lymphoma: t(8;14) in Burkitt's lymphoma,
t(14;18) in follicular lymphoma, and t(ll;14) in diffuse lym
phoma (1, 2). However, these translocations have also been
observed in other B-cell malignancies including ALL,3 CLL,
and MM (3-5).
Apart from morphological classifications of lymphoma and
leukemia, immunological studies of tumor cells using mono
clonal antibodies make it possible to classify B-cell neoplasms
to a certain stage of differentiation. However, the morphologi
cal types and immunological findings are not concordant in
many instances. The morphological, immunological, and cyto-
genetic observations for ALL have been uniformly summarized
to provide clinicians with a series of guidelines to identify these
subtypes and to manage these diseases (6).
In the present study, the chromosomes were examined in 61
patients with B-cell malignancies. Among the clonal karyotypic
changes observed in 35 patients, a rearrangement of chromo
some 14 at band q32 was detected in 26. The 14q+ marker
chromosome resulted from a variety of reciprocal translocations
and the donor sites for the 14q+ chromosome specified the
histológica! types of B-cell malignancies. Therefore, chromo
some rearrangements may have a significant role in diagnosing
B-cell malignancies, and may also be used to predict prognosis.
In addition, molecular genetic studies on these specific re
arrangements may reveal the activation of cellular oncogenes
that were found in some B-cell malignancies.
MATERIALS
AND METHODS
Patients. Chromosome studies of neoplastic B-cells were performed
in 21 patients with NHL (10 males and 11 females), three with HCL
(two males and one female), eight with WM (five males and three
females), and 29 with PCD (16 males and 13 females) between January
1982 and December 1987. All 61 patients were diagnosed histologically,
or hematologically, and immunologically. A histological diagnosis was
based on the findings of biopsied lymph nodes or tumor tissues (21
patients with NHL and one each with WM and PCM) according to the
classification proposed by the Non-Hodgkin's Lymphoma Pathologic
Classification Project (7).
Immunologically, all patients were studied for serum M-protein and
urine Bence Jones protein by an electrophoretic study. In all patients
with NHL (Cases 1-21), all with HCL (Cases 22-24), one with WM
(Case 30), and three with PCD (Cases 53, 60, and 61), immunological
phenotyping was done on single cell suspensions using a panel of
monoclonal antibodies and monospecific antisera against heavy and
light chains.
Cytogenetic Studies. Chromosome analyses were performed as de
scribed previously (8,9). Briefly, a minced cell suspension, bone marrow
aspirate, blood, or peritoneal or pleural fluid was dispersed in 10 ml of
RPMI 1640 medium supplemented with 15% fetal calf serum at a final
concentration of 1 x IO6 cells/ml. The cells were cultured at 37°Cfor
24 or 48 h with 5% CO2 in humidified air, and then exposed to Colcemid
(0.05 Mg/ml) for 60 min. For high resolution banding analysis, the
cultured cells were exposed to 10 ^g/ml of ethidium bromide (Sigma)
for the last 2 h of culture, and then treated with 0.05 Mg/ml of Colcemid
for 15 min. The cells were processed in 0.075 M potassium chloride for
20 min, and fixed with methanol:glacial acetic acid (3:1) and chromo
some preparations were made by an ordinary air drying method. In two
Received 8/18/88: accepted 12/6/88.
The costs of publication of this article were defrayed in part by the payment
patients with HCL (Cases 23 and 24), the cultures of neoplastic cells
of page charges. This article must therefore be hereby marked advertisement in
were exposed to the B-cell mitogen, protein A, of Staphylococcus aureus
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1This work was supported in part by Grants-in-Aid from the Ministry of
strain Cowan 1 (STA) (10) (final concentration, 0.01%), and harvested
by the standard procedure after 24 h of incubation. G-banding with the
Health and Welfare, and the Ministry of Education, Science and Culture of Japan.
2 To whom requests for reprints should be addressed.
trypsin-Giemsa method was done in all instances. Special staining
3The abbreviations used are: ALL, acute lymphoblastic leukemia: NHL, nontechniques, i.e., R, C, and Q banding, were done with base specific
Hodgkin's lymphoma; ML. malignant lymphoma; SL, small lymphocytic; FM,
antibiotics and fluorochromes of chromomycin A3, distamycin A, 4'-6follicular, mixed small cleaved and large cell; FL, follicular, predominantly large
diaminido-2-phenylindole, and actinomycin D for qualified identifica
cell; DSC. diffuse, small cleaved cell; DM, diffuse, mixed small and large cell;
DL, diffuse, large cell; IBL, large cell, immunoblastic; SNC, small noncleaved
tion of marker chromosomes (9). A minimum of 25 well-spread metacell; HCL, hairy cell leukemia; WM, Waldenstrom's macroglobulinemia; PCD,
phases were selected for photography and the chromosomes were
plasma cell disorder; MM, multiple myeloma; PCL, plasma cell leukemia; PCM,
arranged according to the International System for Human Cytogenetic
plasmacytoma; IgH, immunoglobulin heavy chain; IgL, immunoglobulin light
Nomenclature (ISCN, 1985) (11).
chain; CLL, chronic lymphocytic leukemia.
1275
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1989 American Association for Cancer Research.
14q+ MARKER CHROMOSOME
RESULTS
Non-Hodgkin's Lymphoma. The histológica! classification of
the 21 patients was ML-FM in four, ML-FL in one, ML-DSC
in three, ML-DM in three, ML-DL in three, ML-IBL in one,
and ML-SNC in six. All these lymphomas were of B-cell origin.
The specific features of the surface membrane immunoglobulin
are shown in Table 1.
All 21 patients had clonal karyotypic abnormalities. The
modal chromosome number varied from hypodiploid to hyperiripio id; one patient showed hypodiploidy, eight diploidy, 10
hyperdiploidy, and two hypertriploidy. Five patients (Cases 15,
16, and 18-20) had a t(8;14) as a sole abnormality; five (Cases
1, 3,4, 9, and 17) had three to five abnormalities; and 10 (Cases
2, 5-8, 10, 12-14, and 19) had complicated alterations. These
karyotypes had many kinds of chromosomal abnormalities in
cluding trisomy, monosomy, partial duplication, deletion, re
ciprocal translocation, dicentric, or isochromosome.
Rearrangement of chromosome 14 at band q32 was the most
common chromosomal abnormality and was detected in 17 of
IN B-CELL NEOPLASMS
the 21 patients. Among six different donor sites, three were
correlated with histopathological subtypes (Table 2). Firstly, a
translocation between chromosomes 14 and 18, t(14;18)
(q32.3;q21.3), was detected in four of five patients with follicular lymphoma (Cases 1-5) (Fig. la). This translocation was
also found in a patient with ML-DL (Case 12), in whom another
translocation, t(8;22)(q24;ql 1), was observed in all metaphases
examined. In addition, a three-way translocation involving the
same break points as a standard t(14;18) was found in a patient
with ML-DSC (Case 6) (Fig. 2). Secondly, a t(8;14)
(q24.1;q32.3) was found in five of six patients with ML-SNC
(Cases 16-21) and in a patient with ML-IBL (Case 15) (Fig.
le). In the remaining patient with ML-SNC (Case 21),
t(8;22)(q24.1;qll.2)
was seen (Fig. Id). Thirdly, of three pa
tients with ML-DM, two had a t(ll;14)(ql3.3;q32)
(Cases 9
and 11) (Fig. \e).
Other 14q+ marker chromosomes were found as a translo
cation, t(2;14)(q35;q32), in a patient with ML-DSC (Case 7), a
t(2;14)(pl3;q32) in a patient with leukemic ML-DM (Case 10)
(Fig. 3fl), and a t(l;14)(p22;q32) in a patient with ML-DL
(Case 13) (Table 2).
Table 1 Summary of cytogenetic results in 21 patients with non-Hodgkin's lymphoma
Patients are grouped according to the histológica!types based on N-HLPC Project (1982) (7).
Case no.°
FM
Age/sex
Sample
source*
Surface
marker0
Karyotype
l*
59/F
LN
M-K
2
68/M
LN
M-K
3
51/F
LN
M-L
4
49/F
LN
G-L
49, XX, +X, -1.+12, +21, +der(l)t(l;X) (p36.3;qll),
I(14;18)(q32.3;q21.3)
75, XXYY, +2, +5, +5, +9, +10, +12, +12, +13, +15,
+16, +16, +20, t(l;5) (p22;q33), +der(3)t(3;7) (q21;?),
+del (6) (ql3q25), +del(6),+der(7)t(7;?)(p21;?), +der(7),
+del(l I)(ql3q23), del(12)(q21q24), t(14;18) (q32;q21),
+i(17q),+i(17q), +der(19)t(19;?)(ql3;?), +marl, +mar2
47, XX, -4, +8, +der(4)t(l;4)
(ql 2;q35),dup( 11)(q 13q23),t( 14;18)(q32;q21 )
48,XX,+2,+12,t( 14;18) (q32;q21 )
5
61/M
LN
M-L
73, XXY, -Y, +l,+2, +7,+8, +10.+ 13, -14, -15, +16,
75/F
LN
M-L
7»
33/F
LN
M
8*
71/M
BM
M-K
47, XX, -6,-15, +19, del(l)(q42.1), t(5;18;14)
(ql3;q21;q32), +dic(6;15)(ql I;pl3), +del(13)(q22.1)
46, XX, +2, -9, -10, -22, t(2;14)
(q35;q32),+del(6)(q22),+der(22)t(9;22)(q 12;p 11)
52, XY, -1, -6, +11, +18, +19, +22,
t( 1;3)(p21 ;p25),+der( 1)t( 1;1)(p34;q21 ), t(5;9)(q31 ;q34),
+der(9)t(9;?)(q34;?), t(ll;13)(pl3;ql2),
t(14;?)(pl3;?),
+der(21)t(21;?)(q22;?), +mar
DM
9
57/F
LN
M-L
10
59/F
PB
M-L
11
DL
12*
77/F
LN
G-K
53/M
Tumor
G
13
65/F
LN
M-K
14
59/F
LN
G-K
48/M
BM
40/M
9/M
27/F
69/M
71/M
10/M
BM
BM
PB
BM
BM
BM
FL
DSC
6*
IBL
15*
SNC
16
17
18
19
20
21*
47, X, -X, +3, -4, +7, -14, +der(4)t(4;?)
(q31 ;?),+der( 14)t( 11;14)(ql 3.3;q32.3)
49, X,+3, +13, +13, t(X; 3; 18)(q21.2;p24.2;pl 1.3),
t(2; 14)(p 13;q32), t(8; 11)(p23.1 ;p 13)
46,XX,t(l I;14)(ql3.3;q32.3)
49, XY, +7, +8,del(3)(q25), del(6)(q21), t(8;22)
(q24.1;qll), t(14;18)(q32;q21),
+der(18)t(14;18)(q32;q21)
46, XX, -9, -17, -18, -20, t(l;9;16) (q21;ql3;pl3),
t(l;14) (p22;q32), +del(3)(p21), +del(5)(pl3),
del(6)(p21 ),+der( 18)t( 18;?)(p 11;?),+mar
51, X,-X, +5,+8, +9,-21, t(3;l I)(q29;pl3),
t(6; 11Xq23;p 15), +der(7)t(7; 11Xp15;p 15), +mar
46,XY,t(8;14)(q24.1;q32)
M-L
B1+
M-K
M-L
M-K
G-L
46,XY,t(8;14)(q24.1;q32)
48, XY.+l, +19, t(l;7)(q21.3;q22.3), t(8;14)(q24.1;q32)
46,XX,t(8;14)(q24.1;q32)
46,XY,t(8;14)(q24.1;q32)
46,XY,t(8;14)(q24.1;q32)
45, -Y,-4, -21, t(X;5;?)(q28;ql5pl5;?),del(l)(q22q32),
t(3;?)(pl2;?),t(4;20)(q21;pl3),
t(8;22)(q24.1;qll),del(17)(pll),
+der(21)t(21;?)(pl3;?), +der(22)t(8;22)(q24.1;ql 1)
" Patient (*) was previously treated (all others untreated).
b LN, lymph node; BM, bone marrow; PB, peripheral blood; Tumor, tumor in the peritoneum.
' M, IgM; G, IgG; K, kappa; L, lambda; B,*, positive for B,.
1276
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1989 American Association for Cancer Research.
14q+ MARKER CHROMOSOME
Table 2 Association of the donor chromosome sites for the 14q+ markers with
known oncogene! and with subtypes ofB-cell malignancies in 26 patients showing
14q+ markers
chromosomeBreak
I4q+
markers1(14:18)
site18q21.38q24.1gene"bcl-2myc
IN B-CELL NEOPLASMS
cells from case 22, a translocation occurred between chromo
somes 14 and 22 resulting in the formation of both a 14q+ and
a Ph'-like chromosome (Fig. 3ft).
Waldenstrom's Macroglobulinemia. 8 patients were diagnosed
of
No. of cases
disease
observed*FM
by monoclonal increase of the serum IgM level and the presence
of neoplastic lymphoplasmacytoid cells in the marrow. In Case
DSC
30, neoplastic invasion was also found in the blood, lymph
DL
WM
nodes, and pleural fluid. A cervical lymph node was histologiMM
cally classified as ML-SL.
t(8;14)K
SNC
IBLDM
Chromosome studies were carried out on marrow cells. In
bcl-1—IgK——lipini—IgL—Type
Ilql3.3Ip222pl32q353pll6p2114q32.122qll.29Mapped
;DLDMDSCMMPCLHCLHCLHCL1*MM
Case
30, the chromosomes were examined in cells obtained
1:14)t(2;14)t(2;14)t(3;14)t(6;14)K14;14)t(14;22)t(14;?)TotalDonor
from blood, lymph node, and pleural effusion. Three patients
had clonal chromosomal abnormalities (Table 3) and five
showed a normal karyotype. In Case 30, a t(14;18) was shown
in 11 of 25 lymph node cells. In this patient, another
+der(18)t(14;18) was seen (Fig. Ib). Blood and pleural fluid
showed a normal karyotype.
226
Multiple Myeloma and Related Disorders. 29 patients with
°Human Gene Mapping 9 (36).
PCD were examined in this series. The patients were classified
* Three-way translocation (*), t(5;18;14).
on the basis of their diagnoses and clinical status at the time of
chromosome analysis as follows: 25 patients with MM, one
with leukemic MM, two with PCL, and one with PCM.
Chromosome analyses were done on bone marrow aspirates
from 24 patients and five (21%) showed abnormal clones.
Peripheral blood was successfully studied in three patients and
two (one leukemic MM and one PCL, Cases 58 and 60) had
chromosomally abnormal clones. A complex karyotype was
found in specimens of peritoneal fluid from a patient with MM
14
18
18
14
(Case 54) and needle-biopsied tumor tissue from a patient with
solitary nonproducing PCM (Case 61) (Table 3). 21 patients
had neither numerical nor structural aberrations. Among eight
patients who showed chromosomal abnormalities, five had one
or two 14q+ marker chromosomes (Cases 53, 54, 55, 58,
and 60), i.e., t(14;18)(32.3;q21.3), t(3;14)(pll;q32),
t(6;14)
(p21.1;q32) (Fig. I/), or 14q+ markers whose donor chromo
somes were not identified.
8
Chromosomal Abnormalities other than I4q+ Rearrangement
14
22
Detected in Patients with B-Cell Malignancies. Other recurrent
chromosomal abnormalities detected are summarized in Table
4. Abnormalities of 6q were seen in 10 patients, Iq in 10, Ip in
six, lip in six, 7p in four, Xq in four, monosomy for X in
seven, and trisomy for chromosome 12 in five and for chro
mosome 3 in four. Among them, trisomy for chromosome 12
was observed as an additional chromosomal change in four of
eight patients with t(14;18) (Cases 1, 2, 4, and 53).
t
a
?-|4.
i I-1««
IN u
¿Ãa*
6
14
DISCUSSION
Fig. 1. Partial karyotypes from patients with a B coll neoplasm, a and b, a
t(14;18)(q32.3;q2l,3) in a patient with ML-FM (Case 1) and a patient with WM
(Case 30); e, a t(8;14)(q24.1;q32.3) in a patient with ML-SNC (Burkitt's type)
(Case 18); d, a variant t(8;22)(q24;qll) in a patient with ML-SNC (Burkitt's
type) (Case 21);/, a 1(11;14)(ql3.3;q32.3) in a patient with ML-DM (Case 11);
g, a t(6;14)(p21.1;q32.3) in a patient with plasma cell leukemia (Case 60); arrows,
break points involved in reciprocal translocations.
Hairy Cell Leukemia. Diagnosis of HCL was confirmed by
demonstrating the presence of tartrate-resistant acid phosphatase-positive cells in all three patients. The leukemic cells of
these patients were shown to be of B-cell origin. One patient
showed a serum M-component, IgG-K, and the same type of
surface membrane immunoglobulin (Case 22).
These three patients had clonal chromosomal abnormalities
including a 14q+ marker chromosome (Table 3); t(14;22)
(q32.3;ql 1.2) (Case 22), t(14;14)(q32.11;q32.33) (Case 23), and
+der(14)t(14;?)(q32.3;?)
(Case 24). In 11 of 100 metaphase
Clonal chromosomal abnormalities were identified in 35 of
61 patients with B-cell malignancies; all 21 patients with NHL,
all three with HCL, three of eight with WM, and eight of 29
with PCD. Chromosome studies have been successfully per
formed only in a very restricted number of patients with WM
or MM (12). This is because of the very slow proliferation rate
of the neoplastic B-cells. In the present study, rearrangements
involving chromosome 14 at band q32 was observed in 26
patients (Fig. 4, Table 2). Among them, the donor chromosome
and its break point could be identified in 23 patients. Thus, it
was found that certain types of 14q+ rearrangement are asso
ciated with certain types of B-cell malignancies.
A t(14;18)(q32.3;q21.3) was found in eight patients: four of
five patients with follicular lymphoma, and one patient each
with ML-DSC, ML-DL, WM, and nonsecretory MM. The
present study confirmed that this translocation is highly specific
1277
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1989 American Association for Cancer Research.
]4q+ MARKER CHROMOSOME
IN B-CELL NEOPLASMS
(CV
It ir ir v «I
II
13
V
§tvt
«fis
10
v
14
16
15
11
12
17
»4
-19-
21
20
22
X
X
mar
NO5673-80337
Fig. 2. Full karyotype from a patient with ML-DSC (Case 6). Small arrows, three-way translocations, t(5;18;14Xql3;q21;q32).
for follicular lymphoma as was reported previously (13, 14).
However, this translocation has also been found in patients
with B-cell neoplasms other than follicular lymphoma (15-18).
It has not been reported previously that t(14;18) can occur in
patients with WM or MM. On the basis of these findings, in
conjunction with the observation that follicular lymphoma may
be transformed into other types of B-cell malignancies in which
neoplastic cells show immunoglobulin secretion (19, 20), a
number of patients with MM or WM may share a similar
pathogenetic background with follicular lymphoma.
One of the patients with ML-DSC mentioned above exhibited
a three-way translocation involving chromosomes 5, 14, and
18. The long arm of chromosome 5 was translocated to chro
mosome 18, the distal segment of chromosome 18 to chromo
some 14, and the terminal segment of chromosome 14 to
chromosome 5, resulting in a typical 14q+ marker chromo
some. Thus, the translocation of the terminal portion of 18q to
14q is a critical event in the t( 14:18).
A t(8;14)(q24.1;q32.3) was found in five of six patients with
ML-SNC (Burkitt's or non-Burkitt's) and in one with ML-IBL.
Another translocation, t(8;22), affecting the same chromosomal
break point 8q24.1, was seen in one patient with ML-SNC and
another with ML-DL. Interestingly, t(8;22) was seen in com
bination with t(14;18) in a patient with ML-DL. The simulta
neous occurrence of t( 14;18) and t(8;14) has been reported in a
patient with pre-B ALL and another with acute B-cell leukemia
cell line (15, 16). Another type of coexistence has also been
reported in a patient with CLL, in whom t(14;18) and t(2;8)
were detected (21 ). The significance of the concurrent appear
ance of t(14;18) with t(8;14), t(8;22), or t(2;8) remains to be
elucidated in B-cell neoplasia. It has been speculated that the
two translocations do not occur simultaneously, but sequen
tially (21).
A t(l I;14)(ql3;q32) was found in two patients with ML-DM.
In Case 11, the segment 11q 13—»qter
was translocated to 14q32
and vice versa. In Case 9, t(l 1;14) is not reciprocal, resulting in
a trisomy for the segment 1Iql3—»qter.
This translocation has
been reported in MM (22). The t(l 1;14) was reported to occur
recurrently in ML-SL (23), CLL (4), and MM (24).
All three patients with HCL had a 14q+ marker chromo
some, the donor of which was different: chromosome 14 (band
q32.11), 22 (band ql 1.2), and an unknown chromosome. There
are only a few reported cases with chromosomal abnormalities
(25, 26), since most hairy cells are nondividing. Bristo-Babapulle identified a 14q+ marker chromosome in five patients
with HCL (18). The donor sites were different in each case.
1278
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1989 American Association for Cancer Research.
14q+ MARKER CHROMOSOME IN B-CELL NEOPLASMS
Table 3 Summary ofcytogenetic results in patients with hairy cell leukemia, macroglobulinemia, and plasma cell disorders
Patients are grouped according to types of B-cell malignancy.
Case
no.°HCL22
source*PB
60/FSample PB"Surface
23Age/sex60/M
marker'G-K
G-LM-proteinIgG-K(-)Abnormal
24
40/M
PB«
G-K
WM
25-29
30
31
32»
40/F
70/M
70/M
LN
BM
BM
M-K
ND
ND
MM
33-52
53*
49/F
Pleural
effusion
54«
55»
60/F
67/F
BM
Ascites
BM
56
57»
58«
69/M
79/M
62/F
57/M
59/F
PCL
59
60
cells(%f11100Karyotype46,XY,del(l)(q32.lq42.3),t(14;22)(q32.3;qll.2)
100
IgM-K
IgM
IgM
44
40
40
100
(nonsecretory)
ND
ND
BJ-L
BJ-L
SCA
100
100
BM
BM
PB.BM
ND
IgG-K
IgA-K
IgG-K
15
SCA
100
PB
PB
ND
IgG-L
Nonproducing
100
ND
ND
45,X-,-X,+der(5)t(5; 17)(p 15;q2 1),del(6)(q 15q25),
I(14;14)(q32.11;q32.33)
46,XY,-14,+der( 14)t( 14;?)(q32.3;?)
Normal karyotypes
48,XX,+X,t( 14; 18)(q32;q21 ),+der( 18)t( 14; 18)
46,XY,del(15)(q24)
48, XY, -4, -19, +21, +22, t(7;17)(pl5;pl3),
+der( 19)t(4; 19)(q23;ql 3.4), +mar 1
Normal karyotypes
82, XX, -X, -2,+4, -7,+8, +9,+9, -10,-11,+12,
+13, +14, +15, -17, +18, -20, -20, -20.+22,
+der(X) t(X;?)(q28;?), +der(2)t(2;7)(q35;ql 1),
+der(2), +der(7)t(l;7)(q32;p22),
+der( 11)t( 11;?)(q23;?), t( 14; 18)(q32.3;q21.3),
t(14;18), del(16)(ql 1), del(16), +i(16q), +i(16q),
+der(20)t(ll;20)(ql3.3;ql3.1),
+der(20), +der(20),
+der(20)
46,XX,t(I4;18Xq32.3;q21.3)
73.XX : 1p-, 3p-, oq-, 9q+, 11p+, i(17q), 14q+
53, XX : +l,+3, +7, +9, +12, +15, +17, +18, +19,
-22, +der(2)t(2;6)(p25;ql3), +dic(6)(ql 1), +der(8),
+der(l 1), t(l I;?)(pl4;?), +der(14)t(14;?)(q32;?)
47,XY,+14/46,XY,-2,+mar
47,XY,+20,del( 11)(p 11.2)
41 ,XX: t( 1;6Kq44;q 16), t(3; 14)(p 11;q32),
del( 11)(q 14),der(22)t( 12;22)(22qter-22p 12::12q 1112q24::12ql3-l2q24::12ql3-12qter)
Normal karyotype
46,XX,del( 1)(p 13),t(6; 14)(p21.1 ;q32)/45,X-X,del( 1)(p 13),t(6; 14)(p21.1 ;q32)
PCM
6175/FTumorNonproducing10083,XX:7q+,llq+,20q+
°Patients (*) previously treated (all other untreated).
* Stimulated with STA (**) (10).
' ND, not done.
d SCA, single cell abnormality.
14
22
14
Fig. 3. Partial karyotypes of reciprocal translocations between the immunn
globulin heavy chain gene locus and one of the light chain gene loci, a, a
t(2;14)(pl3;q32.3)
in a patient with leukemic ML-DM (Case 10); a
t(14;22)(q32.3;ql 1.2) resulting in 14q+ marker and I'll' chromosome ina patient
with HCL (Case 22).
We identified a novel translocation, t(6;14)(p21.1;q32) in a
patient with PCL (Case 60). Recently, the human homologue,
lipini, of the murine pim-l gene, has been assigned to band
6p21 (27). The hpim gene is expressed in various hematopoietic
cell lines. A case of childhood T-cell ALL was reported, in
which the chromosomal segment, 6p21-pter, was translocated
to the 7q36 band where the T-cell receptor-/3-chain gene has
been assigned (28). It is possible that hpim is also implicated in
the pathogenesis of B cell malignancy.
Chromosomal translocation results in the conjunction of an
oncogene with the immunoglobulin gene in B-cell neoplasm
(29, 30). In our series, 16 patients showed this type of re
arrangement among 26 with the 14q+ marker. However, chro
mosomal translocations occurred between the IgH gene locus
and one of the IgL gene loci in two patients (Cases 10 and 22).
One is t(2;14)(pl3;q32.3) found in a patient with leukemic MLDM. The neoplastic cells showed a surface IgM immunoglob
ulin of X-light chain. The other is t(14;22)(q32.3;qll.2)
in
another patient with HCL. The leukemic cells bore a surface
IgG of the «-lightchain type. Each chromosomal abnormality
has been reported previously: t(2;14) in a child with CLL (31),
whose leukemic cells expressed IgM and IgD-/c membrane
immun*»globulins;and t(14;22) in 3 patients with ALL (32, 33)
and CLL (4). Both of our cases revealed the mismatch between
the IgL phenotype of the neoplastic cells and the gene loci
involved in these translocations. Similar findings were reported
in a few cell lines (34, 35), in which t(8;22) was found in cells
producing the K-light chain. The role of translocations between
the loci for IgH and K-or X-light chains, t(2;14) or t(14;22), in
the pathogenesis of B-cell malignancies remains to be eluci
dated.
In conclusion, we found a variety of 14q+ marker chromo
some in 26 of 35 patients with clonal chromosomal anomalies
in differentiated B-cell malignancy. In NHL, three 14q+ marker
1279
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1989 American Association for Cancer Research.
14q+ MARKER CHROMOSOME IN B-CELL NEOPLASMS
Table 4 Association of recurrent chromosome abnormalities with types ofB-cell malignancies
Chromo
SNC!
some abnor
FL(n
3)2221»11NHL°DM(n
=
(n3
= 3)
=(n=l)411
4)
mality14q32.36qlq18q21.38424.1-XIPlipIlql3.3+12+37pXqFM
WM(n
=3)33)
IBL
512**1
I212*«*213L
(n =
(n = 1)
Total
(35)2610105444
111111MM432111322111PCDPCL(n=l)111PCM
1
1421311DSC(«
611HCL
*, complex translocation (5;18;14); ", combined with t(8;22); **', t(l I;14)(ql3.3;q32.3).
REFERENCES
13
U 2H
15
16
17
W
20
9
10
11
21
22
X
12
Fig. 4. Human chromosome map (Human Gene Mapping 9) (36) of oncogenes, immunoglobulin genes, and chromosomal break points (•and O) in B-cell
neoplasia. O, donor sites of 14q+ marker chromosome. The karyotype represents
Giemsa bands at the approximately 550 bands stage, according to the ISCN 1985
(11).
chromosomes were associated with the morphological classifi
cation, i.e., t(14;18) in ML-FM, t(8;14) in ML-SNC, and
t(l 1;14) in ML-DM. The donor for the 14q+ marker chromo
some originated from the bands of oncogene loci; bcl-2, c-myc,
or bcl-l. However, the t(14;18) was also observed in patients
with ML-DSC, ML-DL, WM, and MM (a single case of each).
A new chromosomal translocation, (6;14)(p21.1;q32.3), asso
ciated with oncogene c-pim, was found in a patient with PCL.
Thus, the 14q+ chromosome was reconstructed between an
immunoglobulin gene and an oncogene, with rare exceptions,
between the IgH gene and one of the IgL genes.
10.
S., Machii, T., Kitani, T., and Tarili, S. Mitogenic response of neoplastic
"hairy cells" to Staphylococcus aureus Cowan 1. Acta Haematol. Jpn., 48:
1042-1052, 1985.
An International System for Human Cytogenetic Nomenclature (ISCN
1985): report of the standing committee on human cytogenetic nomenclature.
Cytogenet. Cell Genet., 1-118, 1985.
12. Mitelman, F. Catalog of Chromosome Aberrations in Cancer, Ed. 2. New
York: Alan R. Liss, Inc., 1985.
13. Yunis, J. J., Oken, M. M., Kaplan, M. E., Ensrud, K. M., Howe, R. R., and
Theologides, A. Distinctive chromosomal abnormalities in histologie sub
types of non-Hodgkin's lymphoma. N. Engl. J. Med., 507:1231-1236,1982.
14. Bloomfield, C. D., Arther, D. C., Frizzerà , G., Levine, E. G., Peterson, B.
15.
ACKNOWLEDGMENTS
16.
The authors are particularly indebted to Professor Tatsuro Takino,
Director of the Third Department of Medicine, Kyoto Prefectura!
University of Medicine, for kindly reviewing the manuscript, and are
also grateful to Dr. James R. Miller for constructive comments on the
manuscript. We thank our colleagues, Dr. Taira Maekawa who per
formed the study of immunologie cell markers, and Yohko Vanume
who provided expert technical assistance.
We are also grateful to the following for offering the opportunity to
study their patients: Professor Atsushi Sawada, Kyoto Prefectura! Uni
versity of Medicine; Professor Teruo Kitani, Associate Professor Tak
eshi Yonezawa, and Dr. Osamu Sugiyama, Osaka University; Dr.
Masanori Shimoyama, National Cancer Center; and Dr. Hiroshi Fujii,
Kyoto First Red Cross Hospital.
Yunis, J. J. The chromosomal basis of human neoplasia. Science (Wash.
DC), 221: 227-236, 1983.
Rowley, J. D. Biological implications of consistent chromosome re
arrangements in leukemia and lymphoma. Cancer Res., 44:3159-3168,1984.
Kaneko, Y., Rowley, J. D., Variakojis, D., Chilcote, R. R., Check, I., and
Sakurai, M. Correlation of karyotype with clinical features in acute lymphoblastic leukemia. Cancer Res., 42: 2918-2929, 1982.
Nowell, P. C, Shankey, T. V., Finan, J., Guerry, D., and Besa, E. Prolifer
ation, differentiation, and cytogenetics of chronic leukemic B lymphocytes
cultured with mitomycin treated normal cells. Blood, 57:444-451, 1981.
Nishida, K., Taniwaki, M., Misawa, S., Abe, T., Takino, T., and Fujii, H.
Translocation (14; 18) found in a patient with multiple myeloma. Cancer
Genet. Cytogenet., 25:375-377, 1987.
First MIC Cooperative Study Group. Morphologic, Immunologie, and Cy
togenetic (MIC) Working Classification of Acute Lymphoblastic Leukemias:report of the workshop held in Leuven, Belgium, September 15-17,
1986. Cancer Genet. Cytogenet., 23: 189-197, 1986.
The Non-Hodgkin's Lymphoma Pathologic Classification Project. National
Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical
usage. Cancer (Phila.), 49: 2112-2135, 1982.
Misawa, S., Horiike, S., Taniwaki, M., Abe, T., and Takino, T. Prefixation
treatment with ethidium bromide for high resolution banding analysis of
chromosomes from cultured human bone marrow cells. Cancer Genet. Cy
togenet., 22: 319-329, 1986.
Taniwaki, M. New chromosome banding techniques with base specific anti
biotics and fluorochromes for qualified identification of marker chromosomes
in leukemia and related disorders. Acta Haematol. Jpn., 48: 1423-1439,
1985.
Tamaki, T., Yonezawa, T., Kanayama, Y., Inoue, R., Kanakura, l '.. Katagiri,
17.
18.
19.
20.
21.
A., and Gajl-Peczalska, K. J. Nonrandom chromosome abnormalities in
lymphoma. Cancer Res., 43: 2975-2984,1983.
Mufti, G. J., Hamblin, T. J., Oscier, D. G., and Johnson, S. Common ALL
with pre-B-cell features showing (8;14) and (14; 18) chromosome transloca
tions. Blood, 62: 1142-1146, 1983.
Tsujimoto, Y., Finger, L. R., Yunis, J. J., Nowell, P. C., and Croce, C. M.
Cloning of the human chromosome breakpoint of neoplastic B-cells with the
t(14;18) chromosome translocation. Science (Wash. DC), 226: 1097-1099,
1985.
Fukuhara, S., Nasu, K., Kita, K., Ueshima, Y., Oguma, S., Yamabe, H.,
Nishigori, M., and Uchino, H. Cytogenetic approaches to the clarification of
pathogenesis in lymphoid malignancies: clinicopathologic characterization
of 14q+ marker-positive non T cell malignancies. Jpn. J. Clin. Oncol., 13:
461-476, 1983.
Brito-Babapulle, V., Pittman, S., Melo, J. V., Parreira, L., and Catovsky, D.
The I4q+ marker in hairy cell leukemia: a cytogenetic study of 15 cases.
Leukemia Res., 10: 131-138, 1986.
Bain, G. D., and Belch, A. Nodular mixed cell lymphoma with monoclonal
gammopathy. Am. J. Clin. Pathol., 76: 832-837, 1981.
Alexanian, R. Monoclonal gammopathy in lymphoma. Arch. Intern. Med.,
135:62-66, 1975.
Geisler, C., Philip, P., Plesner, P., Andersson, P., Zeuthen, J., Guldhammer,
1280
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1989 American Association for Cancer Research.
14q+ MARKER CHROMOSOME IN B-CELL NEOPLASMS
22.
23.
24.
25.
26.
27.
28.
I!., and Hansen, M. M. Simultaneous presence of translocations t(14;18) and
t(2;8) in a case of chronic lymphocytic leukemia. Cancer Genet. Cytogenet.,
22: 35-44, 1986.
Venti, G., Mecucci, C., Donti, E., and Tabilio, A. Translocation t(l 1;14) and
trisomy Ilql3-qter in multiple myeloma. Ann. Genet. (Paris), 27: 53-54,
1984.
Yunis, J. J., Oken, M. M., Theologides, A., Howe, R. R., and Kaplan, M. E.
Recurrent chromosomal defects are found in most patients with non-Hodgkin's-lymphoma. Cancer Genet. Cytogenet., 13:17-28, 1984.
Dewald, G. W., Kyle, R. A., Hicks, G. A., and Greipp, P. R. The clinical
significance of cytogenetic studies in 100 patients with multiple myeloma,
plasma cell leukemia or amyloidosis. Blood. 66: 380-390, 1985.
Khalid, D., Li, Y-S., Flements, R. J., and Hayhoe, F. G. Chromosomal
abnormalities in a case of hairy cell leukemia. Leukemia Res., 5: 431-435,
1981.
Sadamori, V. and Sandberg, A. A. 14q+ and 6q- anomalies in a case with
hairy cell leukemia. Cancer Genet. Cytogenet., 8:89-90, 1983.
Nagarajan, I... Louie, E., Tsujimoto, Y.. ar-Rushdi, A., Huebner. K., and
Croce, C. M. Localization of the human pirn oncogene (PIM) to a region of
chromosome 6 involved in translocations in acute leukemia. Proc. Nati.
Acad. Sci. USA, 83: 2556-2560, 1986.
Raimondi, S. C., Ching-Hon, P., Behm, F. G., and Williams, D. L. 7q32q36 translocation in childhood T cell leukemia: cytogenetic evidence for
involvement of the T cell receptor /j-chain gene. Blood, 69:131 -134, 1987.
29. Klein, G. Specific chromosomal translocations and the genesis of It-cell
derived tumors in mice and men. Cell, 32: 311-315, 1983.
30. Croce, C. M., and Nowell, P. C. Molecular basis of human B cell neoplasia.
Blood, 65: 1-7. 1985.
31. Sonnier, J. A., Buchanan, G. R., Howard-Peebles, P. N., Rutledge, J., and
Smith, R. G. Chromosomal translocation involving the immunoglobulin
kappa-chain and heavy-chain loci in a child with chronic lymphocytic leuke
mia. N. Engl. J. Med., 309: 590-594, 1983.
32. Ayraud, N., Dujardin, P., and Audoly, P. Leucémieaiguëlymphoblastique
avec chromosome Philadelphie: rôleprobable d'une translocation 14-22.
Nouv. Presse. Méd.,4: 3013, 1975.
33. Sandberg, A. A., Morgan, R., Kipps, T. J., Hecht, B. K., and Hecht, F. The
Philadelphia (Ph) chromosome in leukemia. II. variant l'h translocations in
acute lymphoblastic leukemia. Cancer Genet. Cytogenet., 14: 11-21, 1985.
34. Magrath, I., Erikson, J., Whang Peng, J., Sieverts, H., Armstrong, G.,
Benjamin, D., Tricke, T., Alabaster, O., and Croce, C. M. Synthesis of kappa
light chains by cell lines containing an 8;22 chromosomal translocation
derived from a male homosexual with Burkitt's lymphoma. Science (Wash.
DC), 222: 1094-1098, 1983.
35. Hecht, F., Morgan, R., and Hecht, B. K. Unexpected lambda chain expression
in lymphocytic malignancy. Int. J. Radiât.Oncol., //: 267-270, 1985.
36. Human Gene Mapping 9. Paris Conference (1987): ninth international
workshop on human gene mapping. Cytogenet. Cell Genet., 46:1-762,1987.
1281
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1989 American Association for Cancer Research.
Nonrandom Rearrangement of Chromosome 14 at Band q32.33
in Human Lymphoid Malignancies with Mature B-Cell Phenotype
Kazuhiro Nishida, Masafumi Taniwaki, Shinichi Misawa, et al.
Cancer Res 1989;49:1275-1281.
Updated version
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cancerres.aacrjournals.org/content/49/5/1275
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1989 American Association for Cancer Research.