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Jumping Translocations of Chromosome 1q in Multiple Myeloma: Evidence
for a Mechanism Involving Decondensation of Pericentromeric Heterochromatin
By Jeffrey R. Sawyer, Guido Tricot, Sandy Mattox, Sundar Jagannath, and Bart Barlogie
Karyotypes in multiple myeloma (MM) are complex and
exhibit numerous structural and numerical aberrations. The
largest subset of structural chromosome anomalies in clinical specimens and cell lines involves aberrations of chromosome 1. Unbalanced translocations and duplications involving all or part of the whole long arm of chromosome 1
presumably occur as secondary aberrations and are associated with tumor progression and advanced disease. Unfortunately, cytogenetic evidence is scarce as to how these
unstable whole-arm rearrangements may take place. We
report nonrandom, unbalanced whole-arm translocations of
1q in the cytogenetic evolution of patients with aggressive
MM. Whole-arm or ‘‘jumping translocations’’ of 1q were
found in 36 of 158 successive patients with abnormal karyotypes. Recurring whole-arm translocations of 1q involved
chromosomes 5,8,12,14,15,16,17,19,21, and 22. A newly delineated breakpoint present in three patients involved a wholearm translocation of 1q to band 5q15. Three recurrent
translocations of 1q10 to the short arms of different acrocentric chromosomes have also been identified, including three patients with der(15)t(1;15)(q10;p10) and two
patients each with der(21)t(1;21)(q10;p13) and der(22)t(1;22)
(q10;p10). Whole-arm translocations of 1q10 to telomeric regions of nonacrocentric chromosomes included der(12)t(1;12)
(q10;q24.3) and der(19)t(1;19)(q10;q13.4) in three and two
patients, respectively. Recurrent whole-arm translocations
of 1q to centromeric regions included der(16)t(1;16)(q10;q10)
and der(19)t(1;19)(q10;p10). The mechanisms involved in the
1q instability in MM may be associated with highly decondensed pericentromeric heterochromatin, which may permit
recombination and formation of unstable translocations of
chromosome 1q. The clonal evolution of cells with extra
copies of 1q suggests that this aberration directly or indirectly provides a proliferative advantage.
r 1998 by The American Society of Hematology.
C
to the natural evolution of disease progression. Aberrations in
the centromeric regions of chromosomes can result in chromosome instability, which can lead to a generalized breakdown in
normal chromosome segregation, resulting in nondisjunction or
unbalanced translocations during mitosis. The extra copies of
1q present in B-cell acute lymphoblastic leukemia and many
advanced neoplasias may confer a proliferative advantage.13
Although present in a wide variety of tumors, the movement of
chromosome 1q to one or more nonhomologous chromosomes
and the resulting increase in copy number appear to be a special
type of chromosome instability, because it has been reported
only in a small fraction of patients with any given malignancy
as jumping translocations. Unfortunately, the exact mechanisms
by which whole chromosome arms separate and rejoin with
other centromeres, telomeres, or interstitial sites is unknown.
We have analyzed chromosome 1 aberrations in 158 patients
with abnormal karyotypes and have found a subset of patients
with evidence of nonrandom whole-arm 1q aberrations. The
observation that extra copies of 1q occurred in patients with the
decondensation of centromeric heterochromatin prompted an
expanded study of this group. The decondensation of the centromeric heterochromatin of 1q suggests that hypomethylation of
this region may play a role in the somatic pairing, fragility, and
formation of triradial configurations involving the long arm of
chromosome 1. These events may be the precursors to the
subsequent jumping translocations found in some patients. The
striking similarity between chromosome 1q aberrations in MM
patients and those with high-grade lymphomas suggests the possibility of a common mechanism in a number of malignancies.
HROMOSOME 1 aberrations are very common in most
hematologic malignancies and constitute the most common structural aberration in multiple myeloma (MM). Up to
40% of patients with abnormal cytogenetics show chromosome
1 rearrangements,1 which are the most common secondary
findings in the complex karyotypes of MM.1-5 To date no
distinct clinical and prognostic features have been associated
with extra copies of 1q, whereas aberrations involving chromosomes 13 and 11q are associated with a poor prognosis in
MM.6,7 Little is known about the progression of nonrandom
secondary chromosome events involving chromosome 1. Duplications of all or part of 1q and whole-arm translocations of 1q
are widely reported in neoplasia, but the origin of these major
genomic rearrangements remains obscure. Extra copies of 1q
can occur as translocated unbalanced derivative chromosomes,
isochromosomes, or ‘‘jumping translocations’’; however, the
essential genetic characteristic is the same, resulting in partial
trisomies for the 1q segment.8-12
Whole-arm translocations of 1q become jumping translocations when the 1q segment moves (jumps) around the karyotype
to more than one nonhomologous chromosome.
The cytogenetic changes associated with extra copies of 1q
have been attributed in part to cytotoxic treatments and in part
From the Departments of Pathology and Medicine, Arkansas Cancer
Reseach Center, University of Arkansas for Medical Sciences; and the
Cytogenetics Laboratory, Arkansas Children’s Hospital, Little Rock, AR.
Submitted August 14, 1997; accepted October 24, 1997.
Supported in part by Grant No. CA55819 from the National Cancer
Institute, National Institutes of Health, Bethesda, MD.
Address reprint requests to Jeffrey R. Sawyer, PhD, Cytogenetics
Laboratory, Arkansas Children’s Hospital, 800 Marshall St, Little Rock,
AR 72202.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734 solely to indicate
this fact.
r 1998 by The American Society of Hematology.
0006-4971/98/9105-0026$3.00/0
1732
MATERIALS AND METHODS
Bone marrow of MM patients was processed for chromosome studies
as previously described.4 Twenty cells were studied in each case for
routine analysis. An abnormal clone was identified as two or more
metaphases displaying either the same structural abnormality or the
same extra chromosome or at least three cells with the same missing
chromosome. Aberrations were designated according to ISCN.14
Blood, Vol 91, No 5 (March 1), 1998: pp 1732-1741
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CHROMOSOME INSTABILITY IN MULTIPLE MYELOMA
RESULTS
Complete karyotype designations are provided in Table 1.
These data represent a subset of cytogenetic findings in a group
of 427 MM patients previously reported.5 To briefly summarize
this patient population, 187 patients (44%) had normal, 158 had
abnormal (37%), and 82 had inevaluable karyotypes (19%).
Within the subset of 158 patients with abnormal karyotypes, 50
patients (32%) showed aberrations of all or part of 1q in the
myeloma clone. These aberrations thus constituted the most
common recurring secondary abnormalities in our MM patients.
Unbalanced whole-arm translocations were found in 26 patients, whereas jumping translocations where the 1q was
observed on more than one nonhomologous chromosome were
found in 10 patients (Nos. 1,2,3,4,8,9,14,17,22,36).
In decreasing order of frequency, 1q was translocated to
15pter in 10 patients (Fig 1A), 22pter in 6 patients, and to 13pter
and 21pter in 3 patients each. One 1q was translocated to 21qter
in 3 patients. Translocations to nonacrocentric chromosomes
included 1q to 19qter in 5 patients, to 19pter in 2 patients, to
12qter in 3 patients (Fig 1B), to 8pter in 3 patients (Fig 1C), to
9pter in 2 patients, and to 17qter in 2 patients (Fig 1E).
Whole-arm centromere to centromere translocations occurred
most frequently between 16p and 1q in 9 patients.
The association of centromeric decondensation, separation,
and subsequent jumping 1q is illustrated in detail by partial
karyotypes of nine cells each from three different patients.
Patient No. 3 shows the jumping of 1q to 17q and subsequently
to 7q (Fig 2A to I). The instability of chromosome 1 is
associated with partial duplications but also with decondensed
chromosomes 1 crossed at the centromere (Fig 2A to C). The
chromosome crossovers in the decondensed centromeric regions suggest somatic association or pairing of centromeric
sequences. Even the der(17)t(1;17)(q10;q25) fusion chromosome is involved in crossovers with the chromosomes 1 at the
centromere, which also suggests somatic pairing of the centromeric 1q sequences between the chromosomes (Fig 2D and E).
In some cells extreme decondensation of both chromosomes 1
and crossing over shows the fragility of these configurations
(Fig 2F).
Patient No. 22 (Fig 3A to I) shows the sequence of events
leading to the der(19)t(1;19)(q10;p13) with the 1q jumping to
the telomere of the short arm of chromosome 19. First there is
the decondensation of 1qh and apparent separation of 1q in
some cells (Fig 3A), whereas other cells show decondensation
of two copies of chromosome 1 (Fig 3B). The association of the
short arm of 19 in the decondensed region of 1q can be clearly
seen (Fig 3C), as can the association of 19p with an extra copy
of 1q while still in the decondensed regions of a triradial
configuration of 1q (Fig 3D). The best illustration of a triradial 1
configuration and the association of 19p is shown in Fig 3E.
This cell appears to show the formation of an extra copy of 1q
from the triradial and the initial fusion of 19p with the extra
copy of 1q. This type of triradial configuration, which shows an
apparent endoreduplication of 1q and association of the short
arm of chromosome 19 with 1q, indicates the likely origin of
der(19).
Patient No. 26 illustrates centromeric instability not only in
chromosome 1 but also in chromosome 19. In this patient, der
(19) is created by the joining of centromeric sequences rather
1733
than the centromeric telomeric fusions described above. This
patient showed centromeric decondensation and fragility (Fig
4A to C), and many cells showed the crossing over of the
der(19) with a decondensed chromosome 1, again suggesting
somatic pairing of centromeric 1q sequences (Fig 4D to H).
DISCUSSION
The primary numerical chromosome aberrations seen in MM
karyotypes apparently evolve over an extended period of time
as a subclinical phenomenon. In later stages of progressive
MM, cytogenetic evolution takes place, resulting in secondary
chromosomal aberrations commonly involving chromosome 1.
Structural aberrations of both arms involving reciprocal translocations are the most common findings. However, a special type
of whole-arm or jumping translocation somehow including an
extra copy of 1q and its subsequent movement to another
chromosome creates a partial trisomy for the whole long arm.
Whole-arm translocations of 1q are different from jumping
translocations because in jumping translocations the 1q segment
becomes unstable and moves (jumps) around the karyotype to
more than one nonhomologous chromosome. Trisomy for the
long arm of chromosome 1 is common in many types of
cancer15-18 and has been reported previously in leukemias and
lymphomas showing multiple telomeric associations with different chromosomes.13,19-30 Experimental evidence has shown that
dup 1q might be a secondary aberration associated with disease
progression26; however, they may also be primary aberrations in
some cases.27 The correlation of trisomy for 1q with the
progression of malignancy has been correlated with the metastatic potential in colon and renal cell carcinomas, including the
involvement of the SKI oncogene located at 1q21.31,32
The derivative (der) chromosomes we report have been
reported previously, with the exception of the der(5)t(1;5)
(q10;q15) in the present study. The der(5) was found only in
conjunction with other 1q aberrations and thus may constitute a
further unique step in the secondary evolution of the MM
karyotype. The recurring der(15)t(1;15)(q10;q10) in this report
is a rare but nonrandom change also associated with myelodysplastic syndrome and myeloproliferative disorders. This aberration has been reported as the sole aberration in most patients.33,34 The der(16)t(1;16)(q10;p10) has been reported in a
wide variety of malignancies, including breast cancer, Ewing’s
sarcomas, and Wilms’ tumors. This aberration has also been
reported as the sole aberration in some cases, but as a secondary
aberration in most patients.35-38 This whole-arm translocation
has been confirmed by fluorescence in situ hybridization using
probes reacting with alphoid and classic satellite DNA.39 It may
be that the probability of recombination of these centromeric
repeats is favored by the sequence homology shared in the
regions corresponding to the t(1;16) exchange points. The
centromeric regions of chromosomes 1,9,16 and Y contain
satellite III DNA consensus sequences largely consisting of
(GGAAT)n repeats and small clusters of satellite III DNA
interspersed among the alpha-satellite DNA.40 Guanine-rich
motifs, such as telomere sequences (TTAGGG)n, adopt highly
stable intra-strand and inter-strand duplexes and possibly tetraplex structures that may favor recombination in this region.41,42
It has further been suggested that tetra-strand DNA has a
function related to nonhomologous recombination, telomere-
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1734
SAWYER ET AL
Table 1. Summary of Cytogenetic Findings
Patient No.
Karyotype
Translocations of 1q10 to 5q15
1
52,59,XY,2Y,11,add(1)(q32),del(1)(p11),1dic(1;20)(p22;p13), inv(3)(p26q23),t(4;19)(q21;q13.3),15,add(5)(q22),1der(5)t(1;5)
(q10;p15),der(5)t(1;5)(q10;q15),del(5)(p13),16,add(6)(q11),17,17,der(8)t(8;11)(q24;q13)32,1der(8)t(8;11)(q24;q13),
t(1;8)(q10;p23),115,der(16)t(1;16)(q10;p13.3),del(17)(p11),119,120,add(20)(p13),121,add(22)(p11),add(22)(q13)[cp20]
2
57,59,X,2X,der(1)t(1;11)(q10;q10),t(1;8)(q42;p23),1der(5)t(1;5)(q10;q15)32,del(6)(q14q15),17,18,18,111,del(13)(q12q14),115,
115,117,1der(19)t(1;19)(q21;q13.3),120,121,?inv(22)(q12q13)[cp20].
3
46,XX[4]
54,55,X,2X,add(2)(q21),13,15,1der(5)t(1;5)(q10;q15)17,der(7)t(1;7)(q21;q36),i(8)(q10)add(8)(q24.1),1der(8)t(8;15)(q10;q10)
add(8)(q24.1),19,der(11;22)(q10;q10),13,der(16)t(2;16)(q23;p13),der(17)t(1;17)(q10;q25),add(19)(p13),121,121, add(22)(p11),
222[cp16]
Translocations of 1q10 to 8p23
4
44,45,XY,?add(5)(q34),t(5;19)(q31;p11),i(6)(p10),der(8)t(1;8)(q10;p23),t(12;18;20)(q13;q21;p13),del(13)(q13q22),214,der(1;16)
(q10;p10)[cp4]5563,92,XXYY,t(1;2)(q25;q37)32,t(5;19)32,i(6)(p10)32,der(8)t(8;11)(p11.2;q13)32,der(11)t(1;8;11)
(q11;p23;q13)32,del(13)(q12q23)32,214,214,der(1;16)(q10;p10)32[cp5].
46,XY[13]
45,X,2Y[6]
5
43,XY,i(6)(p10),der(8)t(1;8)(q10;p23),213,214,222[4]
46,XY[16]
See patient No. 1
Translocations of 1q10 to 12q24
6
46,XX[18]
44,XX,tas(2;9)(q37;p24),add(8)(p11),der(12)t(1;12)(q10;q24.3),213, 221[2]
7
51,XY,13,17,28,19,der(12)t(1;12)(q10;q24.3),213,14q1, 1der(14)t(11;14)(q11;p11),115,119,121[15]
46,XY[5]
8
46,X[6]
43,XY,21,trp(1)(q12q25),der(1)t(1;8)(q10;q10), der(12)t(1;12)(q10;q24),213,214,add(14)(q32)[14]
9
44,46,XX,t(6;7)(q23;q22),28,der(12)t(1;12)(q10;q24.3),del(13)(q12q21),der(13)t(13;17)(q10;q10),der(14)t(14;17)(q10;q10),117,
119,der(19)t(1;19)(q10;q11)[19]
46,XX[1]
Translocations of 1q10 to 14p11
10
47,XY,19,der(14)t(1;14)(q10;p11.2)[18]
46,XY[2]
11
44,46,XY,del(1)(p31p35),t(8;13)(q24.3;q13),del(12)(p11),del(13)(q14q22),214,der(14)t(1;14)(q10;p11),220[cp6]
46,XY[16]
Translocations of 1q10 to 15p10
12
74,76,XX,1X,1del(1)(p21),add(2)(q27),1add(2)(q27),1der(3)t(3;21)(p11;?q11)32,14,15,15,16,16,del(7)(p15),1del(7)(p15),
t(8;21)(q22;q22),19,19,112,112,1der(15)t(1;15)(q10;p10)32,116,116,117,117,118,118,119,120,120,121,121,
1der(21)t(8;21)(q22;q22),122[cp16]
46,XX[4]
13
46,XY[12]
43,X,2Y,der(4)t(1;4)(q11;q35),213,214,215,1der(15)t(1;15)(q10;p10),221,1der(21)t(1;21)(q11;p11),222[8]
14
46,XY[18]
47,X,2Y,15,t(8;14)(q24;q32),19,213,der(15)t(1;15)(q10;p22),der(16)t(1;16)(q10;p10),119,add(19)(q13)[cp2].
Translocations of 1q to 16p10
See patient No. 4
See patient No. 14
15
41,44,XY,add(1)(q21)32,der(2)add(2)(p24)t(2;3)(q31;p14),add(3)(p21),add(3)(q29),t(5;19)(p15;q13),add(7)(p13),210,213,214,
add(14)(q32),der(16)t(1;16)(q10;p10),del(17)(p11),218,add(21)(p13),add(22)(p11),del(22)(q13)[cp20]
16
46,XY,t(8;14)(q24;q32),del(11)(q12),?der(14)t(11;14)(q13;q11),der(16)t(1;16)(p10;q10)[cp4].
46,XY[13]
(Continued on following page)
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CHROMOSOME INSTABILITY IN MULTIPLE MYELOMA
1735
Table 1. Summary of Cytogenetic Findings (Cont’d)
Patient No.
17
Karyotype
45,46,XY,21,add(3)(q26.2),t(4;9)(q35;p11),add(8)(q22),t(11;14)(q13;q32),add(12)(q22),der(16)t(1;16)(q10;p10),
der(19)t(1;19)(q10;p10)[cp3]
74,88,idem,32[cp8]
46,XY[6]
Translocations of 1q10 to 16p13
See patient No. 1
18
52,XY,17,19,19,111,t(14;17)(q32;q?11),115,der(16)t(1;16)(q10;p13),117,add(18)(p11)[24]
53,idem,18[5]
19
46,XX[13]
44,XX,213,214,add(14)(q32),214,der(16)t(1;16)(q10;p13)[7]
Translocations of 1q10 to 17q25
20
45,X,2X,21,15,16,del(6)(q15),17,add(8)(p11.1),212,213,214,115,add(15)(p11),216,add(17)(p11),der(17)t(1;17)(q10;q25),
add(18)(p11.1),add(19)(q13.4)[cp3]
73,77,XX,2X,21,12,13,15,16,17,17,17,28,add(8)(p11;1),111,111,212,213,214,115,add(15)(p11)32,216,del(16)(q22),117,
der(17)t(1;17)(q10;q25)32,add(18)(p11;1)32,219,120,122[cp7]
46,XX[10]
See patient No. 3
Translocations of 1q10 to 19p13
21
68,71,X,2X,2Y,14,25,add(5)(q31),del(6)(q21),17,17,del(8)(p11)32,213,116,1der(16)t(3;16)(q10;q10),117,218,119,
1der(19)t(1;19)(q10;p13.3),120,221,221,222,1mar[cp17]
46,XY[3]
22
44,47,X,2X,11,del(1)(p13p31),der(7)t(1;7)(q10;p22),add(8)(p23),213, 214,115,115,der(19)t(1;19)(q10;p13.3)[cp8]
46,XX[12]
Translocations of 1q10 to 19q13
23
77,XY,1Y,11,11,del(1)(p13),12,12,13,14,16,17,17,18,19,19,111,111,112,114,add(14)(q32)32,115,116,116,
add(17)(p13)32,1add(18)(q23)32,119,1der(19)t(1;19)(q10;q13.3),120,120,121,121,122,122,1mar[cp9]
46,XY[8]
24
47,48,X,2X,der(2)t(2;3)(p21;p21),add(3)(p21),1del(3)(p23),16,add(8)(q24),del(8)(p11),der(9)t(6;9)(q13;p13),del(10)(q25),
del(13)(q13q22),214,115,216,add(16)(p13),add(17)(p11),del(18)(q12q21),der(19)t(1;19)(q10;q13),add(20)(p13),add(21)(q22),
122,1mar1,1mar2[cp4]
46,XX[16]
Translocations of 1q10 to 19p10
25
46,XY,t(9;12)(q11;q22),t(11;14)(q13;q32),der(19)t(1;19)(q10;p10)7590,92,idem32[cp7]
46,XY[6]
26
50,52,X,2X,13,15,16,17,18,i(8)(q10)32,19,213,der(13)t(9;13)(q11;q11.2),115,119,der(19)t(1;19)(q10;p10),120[cp20]
27
53,54,XY,13,15,16,add(6)(q23),17,t(7;17)(p11.1;p12),28,19,115,119,121,1mar[cp11]
53,54,idem,der(19)t(1;19)(q10;p10)[cp4]
46,XY[5]
28
57,59,XX,1del(1)(p13),12,1del(3)(p13),1der(3)add(3)(q29)t(3;13)(q26;?q12),1i(6)(p10),17,17,19,der(9)add(9)(p24),
1der(10)t(10;?22)(p11.2;?q11;2),i(12)(p10),213,115,1der(15)t(1;15)(q21;p11.1),216,118,1der(19)t(1;19)(q10;p10),
del(20)(q11.1),del(22)(q12),1add(22)(q13)[cp20]
See patient No. 17
29
53,X,2X,del(1)(p13p22),1der(1)t(1;19)(q10;p10)32,13,16,del(6)(q21),19,115,118,121[2]
106,idem32[1]
46,XX[17]
Translocations of 1q10 to 21q22
30
46,XX[14]
47,XX,22,add(2)(q31),119,221,1der(21)t(1;21)(q10;q22)[cp6]
31
46,XX[17]
45,48,X,2X,17,19,213,1der(21)t(1;21)(q10;q22)[cp4]
(Continued on following page)
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1736
SAWYER ET AL
Table 1. Summary of Cytogenetic Findings (Cont’d)
Patient No.
Karyotype
Translocations of 1q10 to 21p11
32
44,X,2X,der(6)add(6)(p25)t(1;6)(q12;q12),?inv(7)(p14p22),del(8)(p11),213,del(20)(q12),der(21)t(1;21)(q10;p11)[cp9]
46,XX[11]
33
143,46,XY,t(1;21)(q21;p11),22,add(6)(q?21),add(7)(p?22),28,19,212,add(13)(p11),add(17)(p?11),119[cp18]
46,XY[2]
Translocations of 1q10 to 22p11
34
52,X,2X,13,15,16,17,der(8)t(?X;8)(?q13;p21),111,115,der(22)t(1;22)(q10;p11.2),1mar[2]
46,XX[13]
35
46,XY[16]
40,43,X,2Y,213,add(14)(q32),218,der(22)t(1;22)(q10;p11)[cp3]
36
46,XY,11,del(1)(p11),t(2;19)(q37;p13;1),inv(3)(p14q29),del(6)(p22),der(6)t(1;6)(q21;q23),add(7)(p22),213,der(16)t(1;16)(q10;q22),
119,der(22)t(1;22)(q10;p11.2)[3]
telomere recombination, and immunoglobulin switch recombination.42
Jumping translocations involving multiple chromosomes are
a rare phenomenon, the mechanisms of which remain obscure.
However, the types of chromosome 1 centromeric decondensation observed in our patients appear to be similar and reminiscent of changes observed in cells treated with the hypomethylating agent 5-azacytidine.43,44 This suggests that undermethylation
Fig 1. Partial karyotypes from six different patients showing examples of recurring 1q aberrations seen in MM. Patient No.14 showing normal
chromosomes 1 on left and der(15)t(1;15)(q10;q10) on right (A). Patient No. 7 showing normal chromosomes 1 on left and der(12)t(1;12)(q10;q24)
on right (B). Patient No. 4 showing normal chromosomes 1 on left, der(8)t(1;8)(q10;p23) in middle, and der(16)t(1;16)(q10;p10) on right (C). Patient
No. 1 showing two normal chromosomes 1 and an extra copy of 1q on left, a der(5)t(1;5)(q10;q15) in the middle, and der(16)t(1;16)(q10;p13) on
right (D). Patient No. 2 showing der(5)t(1;5)(q10;q15) in middle and der(17)t(1;17)(q10;q25) on right (E). Patient No. 21 showing three
chromosomes 1 on left with three normal copies of chromosome 19 and a der(19)t(1;19)(q10;p13) on right (F). Arrows indicate chromosome
fusion points.
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CHROMOSOME INSTABILITY IN MULTIPLE MYELOMA
1737
Fig 2. Partial karyotypes of nine different cells from patient No. 3 showing centromeric heterochromatin decondensation of chromosome 1
and association of 1q heterochromatin with 17q25. Duplications of 1q (open arrow) are found in addition to extra copies of translocated 1q
(closed arrow) (A). Subtle decondensation of chromosomes 1 and crossing over of chromosomes 1 (B and C). Crossing over of der(17)t(1;17)(q10;
q24) with chromosome 1 (arrows) (D and E). An extra free copy of 1q (G). Decondensation of chromosome 1 and der(17) (H). Chromosome 1q has
jumped from der(17) to 7q leaving heterochromatin on 17q24 (arrow) (I).
is associated with the decondensation of the heterochromatic
regions. Hypomethylation could be induced as a side effect of
cytotoxic therapy, have a viral association, or be part of an
unknown process associated with tumor progression.
A viral origin for jumping translocations and juxtacentromeric fragility in neoplasia has been suggested.19 It is
known that gene products of certain DNA cancer viruses
(SV-40, human papilloma virus, and adenovirus) can alter
cellular proteins and affect cell-cycle checkpoints, thereby
inducing karyotype instability.45 A variety of chromosome
aberrations, including telomeric associations, dicentric chromosomes, and aneuploidy, have been induced in human fibroblasts
by the SV-40 virus,46-48 as have jumping translocations.48,49 An
alternative explanation to viral induction could be that, following DNA duplication, the hypomethylated decondensed state of
the paracentromeric heterochromatic regions of homologous
chromosomes preserves the interphase somatic pairing and
accounts for the multiradial associations observed at metaphase.50 The persistent somatic pairing could result in multibranched chromosomes of varying sizes from duplications of 1q
occurring in these cells. In fact, azacytidine-treated cells show
uncoiling and somatic associations and indicate molecular
exchanges between classical satellite-containing regions in
homologous and nonhomologous chromosomes.51,52
As there are several possible mechanisms involved in jumping translocations, our findings suggest that a number of
chromosomal landmarks may be associated with the process of
‘‘jumping copies of 1q.’’ In our patients we found recurrent
centromeric decondensations and centromeric separations as
signs of hypomethylation of the centromeric heterochromatin.
The duplication of part of 1q is often seen in the same patients
who subsequently show duplications of the entire 1q. Decondensed chromosomes 1 frequently cross over apparently as a
result of sequence homology (somatic pairing) in the stretched
regions (Figs 2 to 4). Triradials as seen in patient No. 22 (Fig
3E) are rare events and are believed to arise from the partial
endoreduplication of a chromosome arm.53 Interestingly, the
combination of hypomethylation and the appearance of triradial
chromosome configurations as observed here have been reported elsewhere in both neoplastic and non-neoplastic disorders. A rare pediatric immunodeficiency syndrome (ICF syndrome) shows the most striking array of triradial and multiradial
chromosomes.54 These patients show an embryonic-like methylation pattern of classical satellite DNA and multibranched 1q in
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
1738
SAWYER ET AL
Fig 3. Partial karyotypes of nine different cells from patient No. 22 showing centromeric heterochromatin decondensation of chromosome 1,
formation of triradial configurations, and movement of 1q. Decondensation of centromeric heterochromatin and apparent separation of 1p and
1q of one chromosome 1 (arrow), normal chromosomes 19 on right (A). Decondensation of two chromosomes 1 (B). Decondensation of
chromosomes 1 with chromosome 19p associating in region of decondensation (arrow) (C). Decondensation of 1qh and assocation of 19p13 with
decondensed heterochromatin (arrow); note there are now four copies of 1q (D). Decondensation of 1qh and association of 19p13 with 1qh
(arrow) and an extra copy of 1q. Note clear triradial of chromosome 1 (E). The translocation of 1q to 19p13 as it is seen in the vast majority of cells
(F). The continuing instability of 1q is illustrated by the apparent decondensation of 1q sequences as it is lost from 19p (arrows); note thread-like
chromatin. (G and H). The loss of 1q from 19p is shown by only heterochromatin remaining on 19p (arrow) (I). Note small segments of
heterochromtin left on the short arm of 19 in cells (G and H).
peripheral blood lymphocytes.55 In neoplastic disorders, decondensation of 1q and jumping translocations have been reported
in an HIV-related non-Hodgkin’s lymphoma.30 Although the
factors involved in the induction of the centromeric decondensation may be different, and the resulting clonal expansion is
different, the striking similarity of chromosome triradials is
intriguing.
The hypothesized model of the clonal evolution of tumor-cell
populations suggests that during the cytogenetic progression of
malignancy acquired genetic lability permits the stepwise
selection of variant subclones.56 During this evolution tumorcell populations emerge that may or may not be viable. Nearly
all variants are eliminated, but occasionally one has a selective
advantage and becomes the predominant subpopulation. It is
likely that hypomethylation is induced by a variety of mechanisms. However, hypomethylation appears to be the critical
event associated with the decondensation and subsequent
instability of the classical satellite sequences associated with the
pericentromeric heterochromatin of chromosome 1 (Fig 2). This
decondensation in some patients is apparently followed by
duplication of 1q regions adjacent to the heterochromatin of
chromosome 1 resulting in what presents as triradial chromosomes 1q (Fig 3). These configurations may result from somatic
pairings of chromosome 1 with the resulting loss of 1p and the
subsequent translocation or jumping of the 1q to other chromosomes. The finding of triradial chromosomes in patients is
extremely rare because these configurations are unstable and
probably lost as micronuclei. Apparently, in some patients,
these configurations do not evolve, whereas in other patients the
entanglement of other chromosomes in the decondensed heterochromatic regions adjacent to an extra copy of 1q may cause
chromosome arm exchanges (Fig 4). The highly decondensed
heterochromatin may provide an opportunity for the fusion of
this chromosome segment to other chromosomes because the
hypomethylated segments may favor recombination. Once the
1q has translocated to another chromosome it is likely the only
stable chromosome change to survive from the transitional
(unstable) triradial. Our data suggest a speculative model for
heterochromatin decondensation in the dynamics of 1q translocations (Fig 5).
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Fig 4. Partial karyotypes of nine different cells from patient No. 26 showing centromeric heterochromatin decondensation of chromosomes 1,
formation of triradial configurations, and movement of 1q. Cell showing normal 1s and der(19)t(1;19)(q10;p10) (arrow) (A). Chromosome 1 on
right showing decondensation (arrow) (B). Both chromosomes 1 showing separations of short and long arms (arrows) (C). Somatic pairings of
der (19)t(1;19)(q10;p10) and chromosomes 1 (arrows) (D through H). Subsequent instability of 19p10 and 1q10 (arrow) (I).
Fig 5. Possible model for the decondensation of juxtacentromeric heterochromatin in jumping translocations of 1q. A spectrum of 1qh
decondensations occur in MM cells, ranging from an apparently normal 1qh region (A), to slightly elongated 1qh (B), or highly decondensed and
thread-like 1qh (C). Partial endoreduplication of 1q apparently occurs while heterochromatin is decondensed (D). Fusions with telomeres of
nonhomologous chromosomes may be facilitated by the highly decondensed heterochromatin (E). The origin of a new derivative chromosome
with 1q fused to telomere (F). Condensation of heterochromatin on derivative chromosome (G) creates the appearance of a typical whole-arm
jumping translocation.
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1740
SAWYER ET AL
The equilibrium between proliferation and programmed cell
death in MM cells is believed to be controlled in part by
cytokines. In this respect, growth control of MM cells may be
affected by increased gene dosage related to duplications of part
or all of the long arm. The observation of extra copies of 1q
suggests several possibilities for low-level gene amplification
indicated by the presence of genes related to MM biology. The
interleukin-6 (IL-6) signaling pathway may possibly be affected
by the amplification of the 1q21 region, which is the site of
IL-6RA.57 Other genes of interest in this region include
C-reactive protein (CRP) and amyloid P component (APCS),
both localized to 1q21-23,58 and pre–B-cell leukemia transcription factor 1 (PBX1) at 1q23.59
Chromosome aberrations often have diagnostic and prognostic significance. The roles played by cytotoxic drugs, ionizing
radiation, or oncogenic viruses in the evolution of secondary
chromosomal aberrations in MM are still far from clear. It
seems likely that these factors interact with the cell genome in a
variety of ways to bring about at least a gene dosage effect
caused by the extra copies of 1q. The evolution of centromeric
instability appears to be the precursor for subsequent telomeric
fusions and jumping translocations in some patients. Decondensation and stretching of centromeric heterochromatin is associated with the persistence of somatic pairing, multibranched
chromosome arms, whole-arm deletion, duplication, isochromosomes, and centromeric fragility.52,53,60 The progression of
centromeric destabilization in these patients, from simple
heterochromatic decondensation to subsequent multibranching
and jumping translocations, shows a sequence of events in its
progression. We speculate that hypomethylation-induced pericentromeric heterochromatin decondensation is an initiating
event.
ACKNOWLEDGMENT
We gratefully acknowledge the expert technical assistance of cytogenetic technologists Eddie Thomas, Charles Swanson, Linda Goosen,
Mamie Crowson, Gael Sammartino, Emmett Jones, and Janet Lukacs.
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1998 91: 1732-1741
Jumping Translocations of Chromosome 1q in Multiple Myeloma: Evidence
for a Mechanism Involving Decondensation of Pericentromeric
Heterochromatin
Jeffrey R. Sawyer, Guido Tricot, Sandy Mattox, Sundar Jagannath and Bart Barlogie
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