From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
Plasma
By James
Gould,
Karyotypic
abnormalities
and
correlated
were
evaluable
somy
3.
5.
most
common
scnibed
nine
9.
and
ULTIPLE
Most
four
all
that
because
in
disease
commonly
bow
reported
monosomies
and
tnisomies.2’
cytogenetic
plasma
findings
cell
myeloma
chromosomal
and
anomalies
with
were
of
was
justified
1988
by Grune
the
mainly
Disease
t(1 1 ; 14)
of patients
samples
from
were
1985 and
140
submitted
patients
with
both
cytogenetic
were
conducted
for
type.
Cytogenetic
studies
1986,
unequivocal
status
Inc.
1 . Patient
Characteristics
at cytogenetic
study
3 1
36
45
Relapsing
30
60 (P
Remission
10
40
IgG
60
42
IgA
30
63(P-
22
41
flow
cell
myeloma
cytometnic
on marrow
analysis.
aspirates
collected
chain
only
acetic
acid
Air-dried
fixative
slides
were
methanol:glaciab
acetic
C-bandings
tical
acid
the
ties
A normal
abnormality
Excluded
from
less
with
flow cytometry
metaphases
no clonal
from
to normal
to therapy
sons
the
ratio
were
conducted
all clonal
abnonmali-
15
I 2 patients
also
were conducted
DNA,
DNA
of tumor
Tumor
on
IS
40
Hyperdiploid
85
48
patients.
Hyperdiploid
tnisomies
and
8, 13,
some
samples
commonly
tetnasomies
of chromosomes
2 1 ; monosomies
typically
16, 20,
or 22 (Fig
1 were
found
chromosome
14 had
showed
multiple
5,
11
3,
involved
2). Structural
in 49%
lymphoma
but
of chromo-
without
at q32;
both
(Table
1).
a consis-
the
metaphases.
78%
of
There
was
five
q22 and
of large
q3 1
cell
and
the
a
In
of
remaining
t(8;l4)(q24,q32)
t(1 l;14)(q13;q32)
in the same
On flow cytometny
studies,
hyperdipboidy
, 15,
chromosomes
region
of deletion
(Fig 3).
with
structural
anomalies
a breakpoint
showed
7, 9,
changes
of patients
tent breakpoint
or a common
contrast,
1 3 of I 8 patients
mass
RNA,
index
was
Gl/0
cells
and
cnitenia.’9’#{176}
Statistical
by chi-square
remis-
marrow
with less than
The
intensities
40
25
patients
linear,
had
statistical
excluded.
ofceblubar
content,’6’7
lymphocytes.”
no cbonal
during
in the
5
Diploid
patients
showed
breakpoints
at sites between
(Fig 3). One individual
with a prior
history
examined.
studied
cells
were
by standard
when
metaphases
plasma
of fluorescence
were defined
included
karyotype;
blood
cells with
karyotypic
I 3 patients
immunoglobulin
peripheral
or more
showing
abnormality
analyses
cytoplasmic
defined
were
population,
In samples
among
and a normal
and
three
in
Q-, G-, and/or
methods.’4
Iden-
a cbonal
0
ploidy
1 8, 1 9, and
RBCs.
resuspended
was confirmed
1% monocbonal
Flow cytometnic
and
karyotype
the analysis
than
eliminate
pellet
defined
where
karyotype
detected
to
cell
to standard
cells
required’
reported
was
sion
or more
were
heterogeneity,
the
(1 :1 by volume).
or deletions,
aberrations
detected.
to fix and
using
according
in two
for monosomies
identical
used
mixture
were performed
abnormalities
except
were
prepared
3
.05)
in
RPMI
1640 growth
medium
with
hepanin
and
colcemid
(0.04
zg/mL)
without
mitogens.
Following
20 minutes
of hypotonic
treatment
in 0.06 mob/L KCL, several changes of 3: 1 methanol:glacial
.12)
=
type
Hypodiploid
marrow
Karyotype
46
44
Light
153 bone
plasma
and
of investi-
Unresponsive
DNA
December
with
resistance
consideration
Nonsecretory
February
with
At diagnosis
Protein
with
of certain
protein
myeloma
in patients
associated
early
& Stratton,
Table
of
METHODS
Between
relationship
and
% Abnormal
each with
describes
association
myeloma
and
therapies.
pathogenetic
occurred
protein.
Barlogie
No. Patients
115
structural
one patient
This report
an
Jones
of
as a variety
number
reveals
Bence
Bart
abnormality
activity.’
Translocations
in a large
a
karyotypic
Hypodiploidy
gational
S
suggested
a specific
type.
and
largely
proliferative
have also been reported,3’9”#{176} as has
t(8;l4)
and t(14;18)
translocation.’2”3
the
to therapy.
type
HeCht,
with
been
14, as well
‘
de-
disorder
have
tumor
1 and
only
Barbara
immunoglobu-
abnormalities
of chromosomes
the
translo-
is a malignant
monocbonal
of
protein
in
abnormalities
secrete
this
Tn-
occurred
t(8;14)(q24;q32)
protein
between
1 6 were
Myeloma
Pathak,
115
Translocations
t(8;14)
Sen
IgA
myeloma
karyotype.
1 3 and
in Multiple
Goodacre,
Among
malignancies
with
of
studies
unsuccessful
in multiple
abnormal
MYELOMA
cells
Cytogenetic
changes
an
B cell
association
Angela
features.
abnormalities.
including
The
studied
monosomy
in other
plasma
bin.
1 5 and
Karyotype
Alexanian,
clinical
had
clonal
patients.
M
were
46%
previously
cations.
Raymond
with
patients.
Cell
From
the
University
at
Houston;
Institute
Biomedical
ofTexas,
and
Research
Submitted
June
29,
compani-
Supported
by
Grants
National
Cancer
accepted
No.
of
37161
by
& Tumor
the
Southwest
AZ.
October
CA
and
Hospital
Center
Scottsdale,
1987;
Institute
Anderson
Genetics
Institute,
response
tests.
M.D.
the
8, 1987.
and
a grant
CA
28771
from
the
from
the
Cullen
Trust
Foundation.
RESULTS
Of I 1 5 patients
with evaluable
an abnormal
kanyotype,
which
with IgA or relapsing
myeloma
abnormalities
degree
was
of marrow
Chromosomal
multiple
structural
letions)
Blood,
occurring
Vol
71,
No
unrelated
Address
metaphases,
46% showed
was more
likely
in patients
(Table
1). The frequency
of
to age,
plasmacytosis
sex,
tumor
(Fig
1).
abnormalities
were
usually
changes
(translocations,
in 90%
2 (February),
and
numerical
1988:
pp 453-456
mass,
or
the
reprint
Medicine,
U. T.
Department
ton.
TX
ofHematology
The publication
charge
with
derivatives,
de-
deviations
in 86%
of
to
Bart
Anderson
Barlogie.
Hospital
(Box
MD.
&
55). 1515
Professor
Tumor
Holcombe
of
Institute,
Blvd.
Hous-
77030.
payment.
“advertisement”
complex,
requests
M.D.
indicate
© 1 988
costs ofthis
This
in
article
accordance
article
must
with
were defrayed
therefore
18
U.S.C.
be
in part by page
hereby
§1734
marked
solely
to
this fact.
by Grune
& Stratton.
Inc.
0006-4971/88/7102-0026$3.00/0
453
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GOULD
454
ET AL
00
80
Inii11m
C
e-io
“-20
S
21-30
31-40
PLASMACYTOSIS
MARROW
‘50
41-50
Fig 1 .
Similar
frequency
of abnormal
karyotype
with
ing marrow
plasmacytosis
defined
either
morphologically
abnormal
DNA/RNA
content.
0 Marrow
differential;
Cytometry.
increasor by
B Flow
ij!..
2
U
---
U
-‘-I
1
-if’
U
U
2
correlation
modal
between
DNA-derived
chromosome
number
(modal
chromosome
number
53 patients
with evaluable
dipboidy
occurred
observed
in only
in
DNA
indices
with
some
chromosome
copies.
One
=
and
patient
(DNA
index)
as a karyotype
divided
karyotypes,
by 46; Fig 4).
chromosomal
1 1%,
4% (P
dant
ploidy
expressed
but
.01).
low
Two
DNA
showed
a
content
showed
concon-
tetraploid
range
present
near
haploid
I
was
in the
rearrangements
II
Among
hypo-
patients
karyotypes
1!:
and
index
in
both
11
aberrations.
locus.
number.
Of
four
patients
myeloma
associated
four
type
patients
with
hypodiploid
with
1 ;14)
all produced
t(1 l;14)(q13;q32).
translocation
was
only
light
patients
prior
responses
or
chain
A hypodiploid
present
in eight
Only
responded
subsequent
to
to
study,
patients
in
with
karyoof nine
three
of 13
comparison
with
cytogenet-
chromosomal
revealed
that
aneuploidy
relationship
abnormalities
was
and
noted
disease
as bone disease
or tumor
mass.
Dune
et al,2’ only four patients
between
specific
manifestations,
such
In contrast
to the report
by
showed
a deletion
of the long
in about
karyotypic
the
30%
other
studies.2”
This
marrow
cells accounted
light
ploidy
with
the
with
all
showed
untreated
bone
patients
destruction.
and
those
flow
and/or
the
in detecting
presence
2.0
high-
in assessing
activity.
a close
content
as
(modal
chromosome
number)
ploidy).
This correlation
indicates
was indeed
that of the abnormal
was found
more than twice as
by cytogenetics
can be attributed
cytometry
and
normal
found
in
findings
cytometny
low proliferative
more
in this
patients
with
an abnormal
kanyotype,
was usually
observed
between
DNA
frequently
discrepancy
6, and
found
These
of flow
chromosome
number
between
who had prior chemotherapy.
chromosome
suggesting
identified
suggested
that
normal
kanyotype
aneupboidy.
determined
by cytogenetics
and flow cytometry
(DNA
that the identified
karyotype
cell population.
Hypodiploidy
of
be
incidence
discrepancy
for the
Monosomy
1 3 occurred
in 19 of 43 patients
who had received
prior
chemotherapy
but
not
in any
of ten
previously
untreated
patients
(P = .02). No difference
was evident
in
arm
50%
sensitivity
in tumors
of patients,’
should
to
cytometric
greater
Among
relationship
80%
abnormalities
than
patients
.01).
apparent
Cytogenetic
studies
of myeloma
have
been
difficult
to
perform,
probably
due to low tumor-proliferative
activity.
Prior
flow cytometnic
analyses
of myeloma
marrow
have
frequently
chemotherapy
abnormal
DISCUSSION
IgA
Other
translocations
also found,
including
production.
(23%)
in 29 of 40 other
ics(73%,P=
No
t(8;14)(q24;q32),
protein
(Table
2, Fig 5).
with B cell malignancy
were
patients
or a t(l
either
with
14
Composite
ideogram
showing
distribution
of clonal
on the chromosomes
affected
mostly with structural
Each symbol represents
one patient
with a breakpoint
Fig 3.
breakpoints
at this
chromosome
8
than
by
to the
deletions
of high
flow cytometry.
This
insensitivity
of DNA
of small
DNA
chromosomes
complement
despite
low
[
U)
C
‘S
1.6
1.4
‘S
a-
.s#{149}
SC
0
0
U)
12
;s#{149}s#{149}
s-#..
1.0
U)
0
-C
0.8
0.6
0.8
1.0
KARYOTYPE
Fig 2.
Frequency
and distribution
patients
with abnormal
karyotype.
only.
B
of numeric
abnormalities
in
IgA; 0 IgG; U light chain
Fig 4.
in myeloma
1.2
INDEX
1.4
( Modal
----,
2.0
1.6
No.
Direct
relationship
between
DNA
patients
with abnormal
karyotype.
and
karyotype
index
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
CYTOGENETICS
IN MYELOMA
2.
Table
455
Myeloma
Karyot
ype and Ig Phenotype
Only BJP
No.
IgG
IgA
(8;14)(q24;q32)’
4
0
4
OP=
(11;14)(q13;q32)’
4
1
1
2
B cell
translocations
(14;18)(q32,q21)
1
0
0
Hypodiploidyfl
13
3
4
6P=
Other
anomalies
34
2 1
12
‘.t4.
Two
gammopathy
abnormalities
and
chromosome
tany
1
.001
one
were
patient
number.22
power
of the
cytogenetics
present
with
only
These
two
findings
structural
dividing
especially
kanyotype
gains
some
I 3; and
no
cells
other
IgA
the complemencell analysis,
and
flow
with
cytometry
of complex
numerical
in multiple
myeboma,
3, 5, and 9; loss of chromo-
of chromosomes
of chromosome
structural
1 23 However,
rearrangements
were
identified
than those associated
with B cell neoplasms.
Transloca1 1 ; 1 4) have been described,3’9”0
as have single patients
tions
(
with
t(8;14)
ciations
or t(14;18)(12,13).
with
the
exclusive
protein
and
patients
response
with
rate
ploidy
was
previously
only
among
who
innovative
been
with
the
with
by
low
either
might
drug
content.’
such
should
from
the
early
as high-dose
in many
patients
The
IgA
in
lower
hypodi-
described
presence
help
identify
has
treatactithe
t(8; 1 4)(q24;q32)
with
Burkitt’s
translocation,
lymphoma,
juxtaposition
to
typically
dysregulates
the
associated
gene
myc
immunoglobulin
expression
heavy
by its
chain
by
of
t(8;14)
preferentially
identical
ences
lymphoma
must
be
B cell
and
to explain
the
malignancies.
Thus
gene locus may be affected,
translocation
occurred
at an
leading
(ie,
(ie, during
to endemic
during
isotype
or IgA
and
involvement
molecular
differ-
different
clinical
different
V-D-J
lymphoma
switching)
lymphoma
seem-
depending
early
phase
immunoglobulin
Burkitt’s
have
Despite
myc
myeloma,
myc
commitment
anomalies
myeloma.
aberrations
IgA
present
gene
myc
IgA
and
postulated
of these
was
and
with
cytogenetic
Burkitt’s
the
the
expression
gene.3#{176}Both
myc
kitt’s
gene.29
by arrows.
one
in
RNA
myc
features
ment.24’25
Specific
translocations
have been linked
to oncogene
vation
in certain
human
mabignancies.262’
Thus
is marked
in about
ingly
of
of a marrow
cell showing
multiple
A typical
Burkitt’s
lymphoma-like
fourth
of our patients
with advanced
myeloma
studied
Northern
analysis,
two of whom
showed
rearrangement
occurred
application
to standard
t(8;14).
Enchanced
the
The
which
0-banded
karyotype
and t(8;14)(q24;q32).
translocation.
observed,
melphalan,
resistant
Fig 5.
trisomies
asso-
t(8;14)
with
of hypodiploidy
resistance
DNA
technique
benefit
therapies,
effective
were
of
Bence
Jones
proteinunia.
patients
with
chromosomal
consistent
hypodiploidy
important
phenotype
association
the prevalence
in patients
patients
In addition,
immunoglobulin
such
as
myeloma
of
with
abnormalities
rearrangement
consistent
patients
stress
in tumor
describing
the entire
cell population.
This study
confirms
prior
reports
and
two
BJP.
techniques
assessing
in
.001
1
sites
joining)
and
or at a later
leading
to
of
on whether
of B cell
phase
sporadic
Bun-
myeloma.3’
REFERENCES
I . Barbogie B, Alexanian
R, Dixon D, Smith L, Smallwood
L,
Delasalle
K: Prognostic
implications
of tumor cell DNA and RNA
content in multiple myeboma.
Blood 66:338, 1985
2.
Philip
pboidy
P. Dnivshobm
in multiple
A: G-banding
myeboma
bone
analysis
marrow
cells.
of complex
Blood
aneu-
47:69,
3. Liang
W, Hopper
J, Rowley
JD: Kanyotypic
abnormalities
clinical
aspects
of patients
with
multiple
myeloma
and
panaproteinemic
disorders.
Cancer
4. Philip P: Chromosomes
Genet Cytogenet
2:79, 1980
S.
Philip
P. Dnivsholm
44:630,
A, Nansen
gammopathies.
NE,
Jensen
9. DeWald
myeloma,
7.
Van
ties
den
Berghe
C, Vaerman
in IgG3
myeboma.
H,
Vermaelen
JP: High
Cancer
K,
incidence
Genet
Louwagie
ofchromosome
Cytogenet
1 1:381,
A,
Cniel
abnonmali1984
with
MR:
Non-random
multiple
5:
A,
chromosomal
myeloma.
Hematol
GW,
Kyle
of cytogenetic
plasma
RA,
aberra-
Oncob
2:307,
Hicks
GA, Greipp PR: The clinical
100 patients
with multiple
or amyboidosis.
Blood 66:380, 1985
studies
cell leukemia
in
10. Kuey-Chu
C, Bevan PC, Mattews
JG: Analysis of G banded
karyotypes
in myeloma cells. J Clin Pathol 39:260,
1986
1 1 . Ranni
Chromosomes
and survival
in multiple
myeloma.
Cancer
Genet
Cytogenet
2:243, 1980
6. Fenti A, Panani, Arapakis
G, Sotinios R: Cytogenetic
study in
multiple myeloma.
Cancer Genet Cytogenet
12:247, 1984
Mecucci
MacKenzie
1984
and
related
Kiliman
iP,
associated
significance
Cancer
MK,
Lewis
1976
1979
of monoclonal
8.
tions
findings
1987
12.
NS, Slavutsky
I, Wechsler
in multiple
myeloma.
Cancer
Yamada
K, Shionoya
type 8;14 translocation
Genet Cytogenet
9:67,
13.
Nishida
M,
in a case of plasma
1983
K, Taniwaki
H: Tnanslocation
(14;18)
Cancer Genet Cytogenet
5, Amano
A, Bnieux 5: Chromosome
Genet
Cytogenet
25:309,
M,
Misawa
found in a patient
25:375, 1987
Imamura
Y: A Burkitt-
cell leukemia.
5, Abe
T, Takino
with multiple
Cancer
T,
Fujii
myeboma.
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
GOULD
456
14. Pathak
S: Chromosome
17:25, 1976
I 5. Harnden
GD, Jensen
Human
Cytogenetic
banding
techniques.
iT (eds):
Nomenclature.
J Reprod
An International
Basel,
Med
System
Switzerland,
for
16.
Latreille
J, Barlogie
B, Johnston
D, Drewinko
proliferative
characteristics
athies.
Blood 59:43, 1982
17. Barbogie B, Alexanian
R, Pershouse
L: Cytoplasmic
immunogbobulin
content
Clin Invest 76:765, 1985
1 8.
Barbogie
Meistrich
nancies
19.
Dune
BG,
Cancer
36:842,
1974
Blood
60:851
V, Vela
,
activating
68:208A,
1986(abstr)
C,
Mellard
D,
1980
staging
W,
fob-
Med
Abnormalities
of
G, Trujilbo
of DNA
J, Hart
distribution
37:4400,
adult
J,
abnor-
with
PH,
Res
in Human
1977
K, Alexanian
Dicke
K,
R: High
transplantation
Zagars
G,
for
Spitzer
G,
Rowley
Genetics.
GW,
and
JD:
in,
Noel
NY,
P. DahI
malignant
Chromosomal
Harris
H,
Plenum
Ri,
hematobogic
abnormalities
Hinschhorn
K
in
(eds):
1986, p 1
Spurbeck
JL:
disorders.
Chromosome
Mayo
Clin
Proc
1985
Yunis
Virol
ii:
Genes
32:58,
1985
Dalla-Favera
CM: Human
chromosome
in multi-
23. Ueshima
Y, Rowley JD: Chromosome
studies in patients
multiple
myeboma
and related
panaproteinemias,
in Wiernik
Cancer
in human
production
Croce
R,
lymphoma,
Dewald
kinetics
29.
G:
MM,
and
Advances
609:675,
protein
factor
Spitzer
B: Correlation
findings
Myeloma
B, Alexanian
LeBeau
for multiple
system
A, Dicke
bone marrow
1986
of
5, Horwitz
L: High dose chemoradiothenapy
and autolomarrow
transplantation
for resistant
multiple
myeboma.
abnormalities
and
lymphoma.
26.
27.
malig-
leukemia
malities
cytogenetic
5:719,
1982
E, Mundy
osteoclast
B, Hittelman
Fu
of hematobogic
R, Zanden
Diseases
(in press)
Blood
28.
R:
Blood
L, Drewinko
with
A clinical
P, Alexanian
Barbogie
Smalbwood
Cells
6q and
plc myeloma.
22.
SE:
B, Baum
chromosome
EJ,
B, Hall
Banlogie
leukemia
Freireich
Blood
Salmon
chemotherapy.
Dune
J,
25.
Jagannath
gous bone
gammop-
M, Smallwood
L, Smith
in multiple
myeloma.
J
M: Characterization
cytometry.
McLaughlin
lowing
21.
Latreible
Andreeff
by flow
myeboma.
20.
B,
M,
Banlogie
melphalan
with autobogous
multiple myeloma.
Blood 67:1248,
B, Alexanian
in monoclonal
24.
Schiffen CA (eds): Neoplastic
Livingstone,
1985, p 499
dose
S. Karges,
1985
R: Pboidy and
Canelbos GP, Kyle RA,
the Blood. NY, Churchill
ET AL
8 that
and
chromosomes
R, Bregni
C-MYC
is translocated
in human
cancer.
Prog
M, Enikson J, Patterson
D, Gallo RC,
oncogene
is located on the region of
in Burkitt
lymphoma
cells.
Proc
Nail Acad Sci USA 79:7824,
1984
30. Selvanayagam
P, Bbick M, Narni F, vanTuinen
P. Ledbetter
DH, Abexanian
R, Saunders
GF, Barbogie B: Alteration
and abnormal expression
of the C-MYC
oncogene
in human multiple
myeloma. Blood (in press)
3 1 . Showe L, Croce C: The robe of chromosomal
translocations
in
B- and T-cell neoplasia.
Ann Rev Immunol
5:253, 1987
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1988 71: 453-456
Plasma cell karyotype in multiple myeloma
J Gould, R Alexanian, A Goodacre, S Pathak, B Hecht and B Barlogie
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