Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1732-1741
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
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.
 |
ABSTRACT |
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
whole-arm 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.
| |
INTRODUCTION |
CHROMOSOME 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 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.
| |
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
| |
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.
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| 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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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).
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| 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).
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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).
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| 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).
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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 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).
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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).
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| |
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-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 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 juxta-centromeric
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 2-4). 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 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 tumor-cell
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 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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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.
| |
FOOTNOTES |
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.
| |
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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Abstract
Introduction
Abstract
