Jumping translocations in hematological malignancies: a cytogenetic study of five cases

Article · January 2009with171 Reads
DOI: 10.1016/j.cancergencyto.2008.07.010 · Source: PubMed
Abstract
Jumping translocations (JT) are rare cytogenetic aberrations in hematological malignancies that include unbalanced translocations involving a donor chromosome arm or chromosome segment that has fused to two or more different recipient chromosomes in different cell lines. We report five cases associated with different hematologic disorders and JT to contribute to the investigation of the origin, pathogenesis, and clinical significance of JT. These cases involve JT of 1q in a case of acute myeloblastic leukemia (AML)-M1, a case of Burkitt lymphoma, and a case of BCR/ABL-positive acute lymphoblastic leukemia, as well as a JT of 13q in a case of AML-M5, and a JT of 11q segment in a case of undifferentiated leukemia. To our knowledge, with regard to hematologic malignancies, this study presents the first case of JT associated with AML-M1, the first case of JT involving 13q as a donor chromosome, and the first report of JT involving a segment of 11q containing two copies of the MLL gene, jumping on to two recipient chromosomes in each cell line and resulting in six copies of the MLL gene. Our investigation suggests that JT may not contribute to the pathogenesis but rather to the progression of the disease, and it demonstrates that chromosome band 1q10 as a breakpoint of the donor chromosome 1q is also implicated in AML, not only in multiple myeloma as it has been known until now.
5 Figures
Jumping translocations in hematological malignancies:
a cytogenetic study of five cases
Kalliopi N. Manola
a,
*, Vasileios N. Georgakakos
a
, Chryssa Stavropoulou
a
,
Alexandros Spyridonidis
b
, Maria K. Angelopoulou
c
, Ioanna Vlachadami
d
,
Andreas Katsigiannis
e
, Paraskevi Roussou
e
, Gabriel E. Pantelias
a
, Constantina Sambani
a
a
Laboratory of Cytogenetics, NCSR ‘‘Demokritos’’ Athens, Greece
b
Division of Hematology, University of Patras, Patras, Greece
c
1
st
Department of Internal Medicine
d
Department of Pathophysiology, Medical School, Laikon Hospital, University of Athens, Athens, Greece
e
3rd Department of Internal Medicine, Sotiria Hospital, Medical School, University of Athens, Athens, Greece
Received 16 May 2008; received in revised form 2 July 2008; accepted 14 July 2008
Abstract Jumping translocations (JT) are rare cytogenetic aberrations in hematological malignancies that in-
clude unbalanced translocations involving a donor chromosome arm or chromosome segment that
has fused to two or more different recipient chromosomes in different cell lines. We report five
cases associated with different hematologic disorders and JT to contribute to the investigation of
the origin, pathogenesis, and clinical significance of JT. These cases involve JT of 1q in a case
of acute myeloblastic leukemia (AML)-M1, a case of Burkitt lymphoma, and a case of BCR/
ABL-positive acute lymphoblastic leukemia, as well as a JT of 13q in a case of AML-M5, and
a JT of 11q segment in a case of undifferentiated leukemia. To our knowledge, with regard to he-
matologic malignancies, this study presents the first case of JT associated with AML-M1, the first
case of JT involving 13q as a donor chromosome, and the first report of JT involving a segment of
11q containing two copies of the MLL gene, jumping on to two recipient chromosomes in each cell
line and resulting in six copies of the MLL gene. Our investigation suggests that JT may not con-
tribute to the pathogenesis but rather to the progression of the disease, and it demonstrates that chro-
mosome band 1q10 as a breakpoint of the donor chromosome 1q is also implicated in AML, not
only in multiple myeloma as it has been known until now. Ó2008 Elsevier Inc. All rights
reserved.
1. Introduction
Jumping translocations (JT) are rare cytogenetic aberra-
tions that include unbalanced translocations involving a do-
nor chromosome arm or chromosome segment that has
fused to two or more different recipient chromosomes in
different cell lines [1e3]. They occur in constitutional
chromosome abnormalities, solid tumors, and hematologic
malignancies [3].
JT have been reported in different types of leukemia or
lymphoma. In most of these cases, they occurred as a sec-
ondary change and the long arm of chromosome 1 (1q) was
preferentially involved as a donor chromosome [3e7]. Al-
though they have been associated with poor prognosis, the
origin and the pathogenesis of JT remain obscure. Several
likely mechanisms that explain the formation of the
derivative chromosomes have been proposed, such as viral
infection, chromosome instability, pericentromeric hetero-
chromatin decondensation, shortened telomeres, and illegit-
imate recombination between telomere repeat sequences
and interstitial telomeric sequences, but the mechanism be-
hind their formation remains elusive [3,4,8,9]. Thus, a sys-
tematic analysis of the localization of the chromosomal
breakpoints involved in JT and their possible genetic conse-
quences is a preliminary step toward understanding the
mechanisms and significance of JT [3].
To contribute toward the investigation of the origin,
pathogenesis, and clinical significance of JT, in this report
we describe five cases of different hematologic disorders
* Corresponding author. Tel.: þ30-2106503811; fax: þ30-210
6534710.
E-mail address: pmanola@ipta.demokritos.gr (K.N. Manola).
0165-4608/08/$ esee front matter Ó2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.cancergencyto.2008.07.010
Cancer Genetics and Cytogenetics 187 (2008) 85e94
showing JT. These cases involve JT of 1q in a case of acute
myeloblastic leukemia (AML)-M1, a case of Burkitt lym-
phoma (BL), and a case of BCR/ABL-positive acute lym-
phoblastic leukemia (ALL), as well as a JT of 13q in
a case of AML-M5 and a JT of 11q segment containing
two copies of the MLL gene, jumping on to two recipient
chromosomes in each cell line, in a case of undifferentiated
leukemia (AML-M0).
2. Materials and methods
2.1. Case reports
Case 1: A 28-year-old woman was diagnosed with
AML-M1 in April 2006. After consolidation chemotherapy,
she underwent an one unit cord blood transplantation dur-
ing first complete remission (CR) in August 2006. A bone
marrow sample on day 47 revealed hematologic CR with
complete donor chimerism. In April 2007, a new bone mar-
row examination revealed relapsed disease with 40% blasts,
and cytogenetic analysis showed a JT of 1q. Four months
later, a new cytogenetic analysis exhibited that JT of 1q still
existed in the karyotype while the blood smear revealed
50% blasts. The patient received intensive chemotherapy,
but the blasts persisted. In December 2007, she underwent
a second allogeneic hematopoietic cell transplantation in
refractory relapse. Examination of the new bone marrow
on day 100 revealed CR and complete donor chimerism.
As of the latest follow up in June 2008, the patient was
in CR.
Case 2: A 21-year-old male presented with diarrhea, ab-
dominal pain, and abdominal distention in September 2007.
The patient underwent urgent right hemicolectomy and
end-to-side anastomosis because of a bulky tumor within
the mesenterium. During the next 2 days, the patient’s gen-
eral condition deteriorated. He presented leukocytosis
(white blood cells, 68.710
9
/L) with 70% blasts, anemia
(hemoglobin 7.7 g/dL), and mild thrombocytopenia (plate-
lets 10010
9
/L). Blood and bone marrow immunopheno-
type disclosed monoclonal kappa-restricted B cells with
strong CD20, CD79b, FMC-7, CD10, CD38, and HLA-
DR expression, while TdT and CD34 were negative. The
karyotypic analysis showed t(8;14)(q24;q32) and a jumping
translocation of 1q. A diagnosis of BL was made. The pa-
tient was started on chemotherapy with cyclophosphamide
and prednisolone, per the BFM G-MALL-B-ALL 2002
protocol. His clinical course was complicated by tumor ly-
sis syndrome and multiple episodes of Gram-negative and
Gram-positive sepsis during periods of myelosupression.
However, he was able to continue with the scheduled che-
motherapy combined with Rituximab. He entered a CR af-
ter the second cycle and is currently toward the end of his
treatment, alive and free of disease six months after
diagnosis.
Case 3: A 70-year-old female presented with persistent
fever in January 2006. One month later, a diagnosis of
high-grade non-Hodgkin lymphoma (NHL) was estab-
lished. Immunophenotypic analysis of bone marrow
showed infiltration of large B cells CD20(þ). She was
started on M-CHOP (cyclophosphamide, doxorubicin, vin-
cristine, and prednisone), and after eight cycles of chemo-
therapy, she achieved complete remission in September
2006. She received anti-cd20 as consolidation therapy until
November 2007 and remained in good condition. In Febru-
ary 2008, she presented with leukocytosis, and a diagnosis
of BCR/ABL-positive ALL was made. Cytogenetic analy-
sis revealed a JT of 1q in addition to the Philadelphia trans-
location. She was treated with the intensive chemotherapy
regimens hyper-CVAD (fractionated cyclophosphamide,
vincristine, adriamycin, and dexamethasone) and Imatinib,
but she died of sepsis 17 days later.
Case 4: A 66-year-old male was diagnosed as chronic
myelomonocytic leukemia (CMML) in March 2002. Cyto-
genetic analysis showed a normal karyotype in 20 meta-
phases analyzed. He started on hydroxyurea 2 months
later. In October 2002, he was hospitalized for persistent fe-
ver, and a diagnosis of AML-M5 was established in No-
vember 2002. A new cytogenetic analysis revealed a JT
of 13q as a secondary change in addition to trisomy 8.
The patient was treated with etoposide, but he died of pro-
gressive disease 40 days later.
Case 5: A 55-year old male was admitted because of
anemia and thrombocytopenia in January 2008. The patient
had complained of fatigue for the last 20 days, and a few
days before admission, he had experienced a post-surgery
hemorrhagic event caused by a dental extraction. His past
history was positive for severe aortic valve stenosis. The
physical examination did not reveal hepatosplenomegaly
or lymphadenopathy. The hematologic examination re-
vealed hemoglobin 7.3 g/dL, white blood cells 6.510
9
/
L, and platelets 2310
9
/L. The majority of the leukocytes
were blasts cells, and their immunophenotype defined the
presence of acute undifferentiated leukemia (M0). The
bone marrow aspiration led to dry tap, and the bone marrow
biopsy was pending. A cytogenetic analysis of peripheral
blood revealed a JT of the 11q segment containing two cop-
ies of the MLL gene. The patient was treated with combina-
tion chemotherapy (indarubicin and aracytin), but he failed
to achieve remission. He died of refractory anaemia 45 days
after diagnosis.
2.2. Conventional cytogenetic analysis
Chromosome studies were performed on unstimulated
bone marrow or peripheral blood cells that had been cul-
tured for 24 and 48 hours. Cytogenetic analyses were car-
ried out on trypsin G-banded chromosome preparations.
Imaging and karyotyping were performed by microscopy
and computer imaging techniques in at least 20 metaphase
cells. Karyotypes were described according to the Interna-
tional System for Human Cytogenetic Nomenclature
(ISCN) 2005.
86 K.N. Manola et al. / Cancer Genetics and Cytogenetics 187 (2008) 85e94
2.3. Fluorescence in situ hybridization (FISH)
FISH studies were performed on bone marrow and pe-
ripheral blood cytogenetic specimens using the following
commercial DNA probes: whole chromosome paints spe-
cific for chromosomes 1, 11, 12, and 13 (Cytocell, Cam-
bridge, UK); MYC/IGH t(8;14) (Kreatech, Amsterdam,
Netherlands); a-satellite probes for the centromeres (CEP)
of chromosomes 1, 4, 7, 11, 12, 15, 13/21, 14/22, and 18
(Cytocell); LSI MLL dual-color break apart rearrangement
probe (Vysis Inc., Downers Grove, IL), and subtelomeric
probes for chromosomes 1q, 11q, 12q, 13q, and 21q (Cyto-
cell). All DNA probes were applied following standard pro-
cedures outlined by the manufacturers. Dual-color FISH
images were digitally generated using the Isis FISH imaging
software (MetaSystems GmbH, Altussheim, Germany).
3. Results
3.1. Case 1
On April 6, 2006 chromosomal analysis of the bone
marrow cells from the patient with AML-M1 at diagnosis
showed a normal karyotype in 20 metaphase cells evalu-
ated. One year later, on April 25, 2007, karyotyping demon-
strated multiple clones with a JT of 1q in all 20 metaphases
analyzed, leading to trisomy of 1q in each clone (Fig. 1,A
and B).
The karyotype was described as follows: 46,XX,der(7)t
(1;7)(q11;q11)[10]/46,XX,der(11)t(1;11)(q11;q25)[5]/46,
XX,t(1;6)(p32;q25~q27),der(7)t(7;12)(q11.2~q22;q13~q15),
der(12)t(1;12)(q11~q12;q13~q15)[4]/46,XX,der(15)t(1;15)
(q11;p11)[1].
Whole-chromosome paint probe for chromosomes 1 and
a-satellite probe for the centromeres of chromosomes 7, 11,
and 12 confirmed JT of 1q to chromosomes 7, 11, and 12.
Moreover, FISH analysis showed a hybridization signal of
the a-satellite probe for the centromere of chromosomes
1 at the fusion ends of the derivative chromosomes 7 and
11, which was formed as a result of a JT, supporting the
translocation of the whole arm of chromosome 1, the cen-
tromere fusion of chromosomes 1 and 7, and the dicentric
nature of chromosome 11 (Fig. 1C). On the contrary, the
derivative chromosome 12 did not show the hybridization
signal of the a-satellite DNA of 1p11.1~q11.1, supporting
the G-banding breakpoint assignment of the donor chromo-
some 1 to 1q11~q12. The derivative chromosome 7 in the
clone with the der(12)t(1;12) was hybridized with the probe
for the centromere of chromosomes 7 and the whole chro-
mosome paint probe for chromosome 12, indicating that the
der(7) has resulted from a translocation of 12q to the long
arm of chromosome 7. Subtelomeric 12q probe in the same
clone gave one signal on the normal chromosome 12 and
one on the der(7)t(7;12), confirming the origin of der(7).
The LSI MLL dual-color break-apart rearrangement
probe showed a normal pattern of hybridization in 200
interphase nuclei. Analyzing metaphases with
der(11)t(1;11), one of the two signals for the MLL gene
on 11q23, was found on the normal chromosome 11, and
the other was detected on the derivative chromosome 11
(data not shown). In addition, the subtelomeric 11q probe
in the same clone also gave one signal on the normal chro-
mosome 11 and one on the der(11)t(1;11), indicating that
the breakpoint of the der(11) was distal to subtelomere
11q (Fig. 1D). According to this new FISH information,
the karyotype may be rewritten as follows:
46,XX,der(1;7)(q10;p10) [10]/46,XX,dic(1;11)(p11;q25)[5]/
46,XX,t(1;6)(p32;q25~q27),der(7)t(7;12)(q11.2~22;q13~q15),
der(12)t(1;12)(q11~q12;q13~q15)[4]/46,XX,der(15)t(1;15)
(q11;p11)[1].
Four months later, a new chromosomal analysis of unsti-
mulated peripheral blood cells presented the following karyo-
type: 46,XX,t(1;6)(p32;q25~q27),der(7)t(7;12)(q11.2~q22;
q13~q15),der(12)t(1;12)(q11~q12;q13~q15) [22]/46,XX,der
(1;7)(q10;p10)[2]/46,XX,dic(1;11)(p11;q25)[1].
3.2. Case 2
Chromosomal analysis of the bone marrow cells of the
patient with Burkitt lymphoma at diagnosis showed com-
plex chromosomal abnormalities with several abnormal cell
sublines. All the abnormal clones were characterized by
t(8;14)(q24;q32), one clone had an additional ring chromo-
some, another one had a partial duplication of 1q, and the
remaining clones had a JT of 1q (Fig. 2, A and B). The kar-
yotype was described as follows: 46,XY,t(8;14)(q24;q32)
[7]/46,idem,þr[10]/46,idem,dup(1)(q21;q32)[6]/46,idem,
der(13)t(1;13)(q12;q34)[4]/46,idem,der(21)t(1;21)(q12;q22)
[3]46,idem,der(14)t(1;14)(q12;p11)t(8;14)(q24;q32)[3]/ 46,
idem,der(18)t(1;18)(q12;q22~q23)[1]/46,XY[6].
The paint probe for chromosome 1 and a-satellite probes
for the centromeres of chromosomes 13, 14, and 21 con-
firmed clonal JT of 1q jumping onto 13q, 14p, and 21q, result-
ing in partial trisomies for the 1q segment. FISH studies did
not show the hybridization signal of the a-satellite probe for
the centromere of chromosomes 1 at the fusion ends of the
derivative chromosomes 13, 14, and 21 formed as a result
of JT, exluding the dicentric nature of these derivative chro-
mosomes. The MYC/IGH fusion probe gave two fusion sig-
nals, and two single-color signals in 40% of interphase cells
analyzed, confirming t(8;14)(q24;q32). The ring chromo-
some was hybridized with boththe paint probe and the centro-
meric probe for chromosome 1 (Fig. 2C). Moreover, FISH
studies showed the absence of signals for 13q subtelomeric
probe at the fusion ends of the derivative chromosome 13
and the absence of signal for 1q subtelomeric probe on the
ring chromosome 1 (Fig. 2D).
3.3. Case 3
On February 7, 2008, during the transformation of NHL
to ALL, chromosomal analysis of bone marrow cells
87K.N. Manola et al. / Cancer Genetics and Cytogenetics 187 (2008) 85e94
revealed a JT of 1q in addition to the Philadelphia translo-
cation (Phþ)(Fig. 3, A and B). The karyotype was de-
scribed as follows: 46,XX,t(9;22)(q34;q11.2)[29]/46,idem,
der(4)t(1;4)(q12;q31)[5]/46,idem,der(18)t(1;18)(q12;q23)
[2]/46,idem,der(5)t(1;5)(q12;q22~q31)[1].
Unfortunately, no material was available for FISH analysis.
According to an expanded cytogenetic study of these
three cases with JT of 1q in 200 metaphases showed that
only the patient with BCR/ABL-positive ALL in case 3
showed increased constitutional heterochromatin of chro-
mosome 1, while the length of the heterochromatin region
of both homologous chromosomes 1q of the other two pa-
tients did not seem to differ cytogenetically, neither in
metaphases with JT nor in metaphases without JT. None
of these three patients showed formation of triradial config-
urations involving the long arm of chromosome 1 or cross-
ing over of the derivative chromosomes with a decondensed
chromosome 1.
Fig. 1. (A) Complete G-banded karyogram showing 46,XX,t(1;6)(p32;q25~q27),der(7)t(7;12)(q11.2~q22;q13~q15),der(12)t(1;12)(q11~q12;q13~q15). (B)
Partial G-banded karyograms from four cells showing der(1;7)(q10;p10), dic(1;11)(p11;q25), der(12)t(1;12)(q11~q12;q13~q15), der(15)t(1;15)(q11;p11). (C)
G-banded metaphase FISH showing the centromere fusion of chromosomes 1 and 7 and the dicentric nature of der(11)t(1;11). Red signal corresponds to
CEP1, whereas the green signal corresponds to CEP 7 and CEP 11. (D) FISH analysis demonstrating subtelomeric 11q probe on der(11), as viewed with
the inverted DAPI filter. Red signal corresponds to CEP 11, whereas the green signal corresponds to the subtelomeric 11q probe.
88 K.N. Manola et al. / Cancer Genetics and Cytogenetics 187 (2008) 85e94
3.4. Case 4
Chromosomal analysis of bone marrow cells of the pa-
tient with CMML at diagnosis showed a normal karyotype.
Eight months later, at the transformation of CMML to
AML-M5, a new cytogenetic analysis revealed a jumping
translocation of 13q in addition to trisomy 8 (Fig. 4,A
and B). The karyotype was described as follows: 47,XY,þ8,
der(14)t(13;14)(q12;q32)[21]/47,XY,þ8,der(10)t(10;13)(p13
~p15;q12)[4]/47,X,der(Y)t(Y;13)(q12;q12),þ8[3]/47,XY,þ8,
der(1)t(1;13)(p36.3;q12)[2]/47,XY,þ8,der(4)t(4;13)(q35;
q12)[2]/46,XY[1].
No material was available for FISH analysis.
3.5. Case 5
Karyotyping of the unstimulated peripheral blood cells
of the patient with AML-M0 at diagnosis displayed com-
plex chromosome abnormalities with three abnormal cell
sublines and a JT of a segment of unknown origin, always
on the short arm of chromosome 13 at band p11, but also in
another recipient chromosome in each cell line (Fig. 5,A
and B). The karyotype was described as follows:43,X,e
Y,add(3)(p25),e5,þ13,add(13)(p11)x2,e15,e16,e17,
Fig. 2. (A) G-banded bone marrow karyogram showing 46,XY,t(8;14)(q24;q32),der(13)t(1;13)(q12;q34). (B) Partial G-banded karyotypes from six cells
showing der(13)t(1;13)(q12;q34), der(21)t(1;21)(q12;q22), der(14)t(1;14)(q12;p11)t(8;14)(q24;q32), and der(18)t(1;18)(q12;q22~q23) as a result of JT of
1q, dup(1)(q21q32), and r(1). (C) Partial FISH karyotype showing the ring chromosome hybridized with both the paint probe (green signal) and the centro-
meric probe (red signal) for chromosome 1. (D) Partial FISH karyotype showing der(13) and r(1) indicated by arrows, not hybridized with subtelomeric 13q
probe (green) and subtelomeric 1q probe (green), respectively. The red signal corresponds to CEP1 and CEP13.
89K.N. Manola et al. / Cancer Genetics and Cytogenetics 187 (2008) 85e94
e20,þmar1,þmar2[6]/42,X,eY,add(3)(p25),e5,add(13)(p11),
e15,e16,e17,e20,add(22)(p11),þmar1,þmar2[4]/42,X,e
Y,add(2)(q37),add(3)(p25),e5,add(13)(p11),e15,e16,e17,
e20,þmar1,þmar2[2]/46,XY[8].
FISH analyses using the paint probe for chromosome 11
and a-satellite probes for the centromeres of chromosomes
13 and 21 showed the donor segment of JT, the origin of
which could not be identified by conventional cytogenetics,
to be of chromosome 11 origin and confirmed the JT of 11q
to chromosomes 13p and 22p (Fig. 5C). The LSI MLL dual-
color break-apart rearrangement probe showed two signals
for the MLL gene on each translocated segment of chromo-
some 11q and one signal on each normal chromosome 11,
resulting in six copies of the MLL gene in the karyotype
(Fig. 5D). Moreover, the derivative chromosomes 13 formed
as a result of JT were not hybridized with an a-satellite probe
for the centromere of chromosome 11, demonstrating that
the derivative chromosomes were not dicentrics (Fig. 5D).
According to this new FISH information, the derivative
chromosomes as a result of the JT may be redefined as fol-
lows: der(13)add(13)(p11).ish dup(11)(q13q21)(wcp11þ)
dup(11)(q21q23)(MLLx2), der(22)add(22)(p11).ish dup(11)
(q13q21)(wcp11þ)dup(11)(q21q23)(MLLx2) and der(2)add
(2)(q37).ish dup(11)(q13q21)(wcp11þ)dup(11)(q21q23)
(MLLx2).
4. Discussion
In this study, we have presented five more cases of JT
associated with different hematopoietic malignancies
(Table 1).
In case 1, a JT involving 1q and jumping on to 7q, 11q,
12q and 15p was observed when the patient with AML-M1
relapsed (Fig. 1, A and B). The dicentric nature of the de-
rivative chromosomes 11 and the centromere fusion of
der(1;7) indicates the G-banding breakpoint of the donor
chromosome 1 to be located at band 1q10 in the relevant
clones (Fig. 1C), constituting the first report to our knowl-
edge of a JT in which band 1q10 is implicated in AML.
Band 1q10 has been reported only in multiple myeloma,
while bands 1q11~1q21 have been implicated in all hema-
topoietic subtypes [3]. The presence of the dicentric chro-
mosome could be attributed to the patient’s previous
treatment with alkylating agents as an increased frequency
of dicentric chromosomes (including those with involve-
ment of chromosome 1q, as described in our case) has been
reported in therapy-related AML [10,11]. The detection of
JT with only a different portion of the abnormal clones 4
months later, a period of time during which the patient
had received no chemotherapy, showed that JT is probably
not a transient event in hematologic malignancies. The
Fig. 3. (A) G-banded bone marrow karyogram showing 46,XX,der(4)t(1;4)(q12;q31),t(9;22)(q34;q11.2). (B) Partial G-banded karyogram from three cells
showing der(4)t(1;4)(q12;q31), der(18)t(1;18)(q12;q23), and der(5)t(1;5)(q12;q22~31).
90 K.N. Manola et al. / Cancer Genetics and Cytogenetics 187 (2008) 85e94
variation in the size of the donor segment 1q in this case is
in line with the report by Andreasson et al. [12], which
shows that JT are highly unstable, showing great variation
in the size of the donor segment, and reflecting that the gain
of 1q is important rather than the breakpoint near the cen-
tromere [12]. The cytogenetically normal karyotype at di-
agnosis and the detection of JT almost 1 year after
diagnosis suggest that JT could not contribute to the path-
ogenesis of AML-M1.
In case 2, involving the young patient with BL, the ini-
tial chromosomal abnormality was t(8;14)(q24;q32), while
partial duplication of chromosome 1q was the secondary
aberration, which is the most frequent secondary change as-
sociated with t(8;14)(q24;q32) in BL and appears to be
linked to disease progression [13e16]. JT of 1q to chromo-
somes 13q, 14p, 18q, and 21q seem to be created after du-
plication of 1q, and at the time, it was determined that the
patient already had a very aggressive clinical course (Fig. 2,
A and B). The ring chromosome that consisted of chromo-
some 1 material and the chromosome 1 centromere, but
without the subtelomeres of 1q, may represent an alterna-
tive form of trisomy 1q (Fig. 2, C and D). The structure
and formation of ring chromosomes in leukemia have been
poorly investigated even though the presence of these cyto-
genetic abnormalities has been related to a poor prognosis
[17]. The two previously reported cases of BL and JT were
also associated with JT of 1q, in addition to t(8;14), and
they had a very aggressive clinical course, as our case did
[13,18].
In case 3, a JT of 1q jumping on to 4q, 5q, and 18q was
detected in the transformation of NHL to BCR/ABL-posi-
tive ALL (Fig. 3, A and B). The initial chromosome abnor-
mality was chromosome Ph. The clinical course was very
aggressive and the patient died shortly after diagnosis and
detection of JT. All the previous reported cases also had
a JT of 1q, as our patient did, which suggests that the asso-
ciation of BCR/ABL and JT of 1q in ALL may not be ran-
dom [19e22].
In case 4, a JT involving the 13q12~qter segment jump-
ing onto 1p, 4q, 10p, 14q, and Yq, leading to a partial tri-
somy of 13q in each cell line, was observed at the time
when CMML was transforming to AML (Fig. 4, A and
B). All the abnormal clones with JT also had trisomy 8,
indicating that JT was the secondary acquired chromosomal
abnormality. The previously reported data showed a prepon-
derance of JT with trisomy 8 in AML-M5; a review of the
literature showed that 7/12 reported AML cases with JT
were AML-M5 involving male patients, and 5 of them were
associated with trisomy 8, as in our case [23e25]. To the
best of our knowledge, a JT involving 13q as a donor
chromosome has not been reported in hematologic
malignancies.
Fig. 4. (A) G-banded bone marrow karyogram showing 47,XY,þ8,der(14)t(13;14)(q12;q32). (B) Partial G-banded karyograms from five cells showing
der(14)t(13;14)(q12;q32), der(10)t(10;13)(p13~15;q12), der(Y),t(Y;13)(q12;q12), der(1)t(1;13)(p36.3;q12) and der(4)t(4;13)(q35;q12).
91K.N. Manola et al. / Cancer Genetics and Cytogenetics 187 (2008) 85e94
Case 5 revealed a JT of a duplicated 11q segment, con-
taining two copies of the MLL gene in a patient with AML-
M0 (Fig. 5,AeD). Each cell line had two recipients of the
donor chromosome segment and one of them was always
chromosome 13, resulting in six copies of the MLL gene.
JT of 11q is very rare phenomenon, with only two known
cases described until now. The first reported patient was
a male with AML-M5a and a JT of 11q resulting in four
copies of the MLL gene in each clone. He died 48 hours
after presentation, before any treatment could be
Fig. 5. (A) G-banded peripheral blood karyogram showing 43,X,eY,add(3)(p25),e5,þ13,add(13)(p11)x2,e15,e16,e17,e20,þmar1,þmar2. (B) Partial G-
banded karyograms from five cells showing der(13)add(13)(p11).ish dup(11)(q13q21)(wcp11þ)dup(11)(q21q23)(MLLx2), der(22)add(22)(p11).ish
dup(11)(q13q21)(wcp11þ)dup(11)(q21q23)(MLLx2), and der(2)add(2)(q37).ish dup(11)(q13q21)(wcp11þ)dup(11)(q21q23)(MLLx2). (C) FISH on meta-
phase cells using the paint probe for chromosome 11 (green) and a-satellite probes for the centromeres of chromosomes 13 and 21 (red) showed the donor
segment of JT to be of chromosome 11 origin. (D) FISH on metaphase cells showing two signals for the intact MLL gene [overlapping red/green (yellow)
fusion signal] on each translocated segment of chromosome 11q indicated by the long arrow and one signal on each normal chromosome 11, resulting in six
copies of the MLL gene. Chromosome 11 a-satellite probe (green) gave signals on the centromere of both normal chromosomes 11, but not on the derivative
chromosomes, demonstrating that the derivative chromosomes were not dicentics.
92 K.N. Manola et al. / Cancer Genetics and Cytogenetics 187 (2008) 85e94
administered [1]. The second was a female patient with sec-
ondary AML and a JT of 11q as a secondary change in ad-
dition to der(9)t(9;11), with multiple recipients in each cell
line, leading to a tetrasomy or a pentasomy of 11q. She died
2 months after diagnosis [2]. Our patient had a very aggres-
sive clinical course and died of refractory anaemia 45 days
after diagnosis without reaching remission. The only
known reported case of AML-M0 with JT involved a 10-
month-old female with a JT of 1q, who died 7 months after
diagnosis [13].
Billuic et al. [22] suggested a possible association be-
tween autoimmune disease or autoimmune disease thera-
pies and hematologic malignancies with JT, which was
not confirmed in our study because none of our patients suf-
fered from an autoimmune disease [23].
JT usually result in trisomy for the donor chromosome
segment and in partial deletions of the recipient chromo-
somes. In our cases, JT of 1q, 13q, and 11q, partial dupli-
cation of 1q, and the supernumerary ring chromosome 1
support gene overrepresentation of several genes mapped
on these segments. Segmental jumping translocations and
formation of ring chromosomes have been demonstrated
to be two additional mechanisms to double minutes and ho-
mogeneously staining regions leading to gene amplification
[26].
In the present study, increased constitutional heterochro-
matin of chromosome 1 was noticed only in case 3, while
no patient showed pericentromeric heterochromatin decon-
densation or formation of triradial configurations involving
1q in all analyzed metaphases with or without JT, as re-
ported previously [8,19]. Since JT has been reported in
cases with and without increased constitutional heterochro-
matin of chromosome 1 and different breakpoints on the
donor chromosome 1q (1q11~q21) have been involved in
JT, it seems that increased constitutional heterochromatin
of chromosome 1 and decondensation of pericentromeric
heterochromatin of 1q could not be the main cause of JT.
Thus, the large constitutive heterochromatin region of chro-
mosome 1 and the low level of DNA repair in human chro-
mosome 1 heterochromatin [27] could possibly account for
the fragility of band 1q12, which is commonly involved in
leukemia but not for the main cause of JT.
It has been demonstrated that telomeric regions of hu-
man chromosomes display elevated rates of mitotic recom-
bination, and it has been suggested that shortened telomeres
of cancer cells may favor the occurrence of JT [4,19].In
some JT cases, it has been shown that the telomeric se-
quences were maintained [4,5], but not in other cases
[24]. In an attempt to investigate if the subtelomeres of
the recipient chromosomes were retained at the fusion ends
of the derivative chromosomes, we found that in the patient
with AML-M1, the subtelomeres of 11q were retained at
fusion ends of the der(11), while in the patient with BL,
the subtelomeres of 13q on the der(13) were lost. The con-
servation of subtelomeres in some cases of hematologic
disorder and their loss in others may result from the chro-
mosomal instability associated with progression of the
malignant process.
In case 1, JT was not transient, but persisted in the kar-
yotype four months after its initial detection, indicating that
JT is unlikely to be a simple reflection of the chromosomal
instability. The appearance of JT could not possibly be at-
tributed to previous cytotoxic treatments because in some
cases, including the present cases 2 and 5, the patients
had not received any previous cytotoxic therapy. Further-
more, in all the reported cases presented in this study, JT
are found as secondary changes, during the course of the
disease, or at the transformation stage of leukemias, and
all patients had an aggressive clinical course at the time
of their detection. Thus, our investigation suggests that JT
Table 1
Demographic, clinical and cytogenetic characteristics of the reported cases with JT
Chromosomes involved in JT
Pt Age (y) Sex Diagnosis
Disease status
at the detection
of JT Donor Recipient Treatment history Outcome
1 28 F AML-M1 R 1q 7q, 11q, 12q,15p Two allogeneic hematopoietic
cell transplantations
Alive in
CR (14m)
2 21 M BL R 1q 13q, 14q, 18q, 21q, Chemotherapy with cyclophosphamide
and prednisolone
Alive in
CR (8m)
3 70 F NHL /BCR/
ABLpositive ALL
R 1q 4q, 5q, 18q M-CHOP for NHL, anti-CD20 as
consolidation therapy, intensive
chemotherapy regimens with
hyper-CVAD and Imatinib for ALL
Died(0.6m)
4 66 M CMML/AML-M5 R 13q 1q, 4q, 10p, 14q, Yq, Hydroxyurea for CMML and
etoposide for AML-M5
Died(1.3m)
5 55 M AML-M0 R 11q 2q, 13p, 22p, Indarubicin and aracytin Died(1.5m)
Abbreviations: Pt, patient; y, years; m, months after detection of JT; M, male; F, female; AML, acute myeloblastic leukemia; BL,
Burkitt lymphoma; NHL, non Hodgkin lymphoma; CMML, chronic myelomonocytic leukemia; ALL, acute lymphoblastic leukemia;
CR, complete remission; R, relapse; M-CHOP, (cyclophosphamide, doxorubicin, vincristine, prednisone); hyper-CVAD, (fractionated cyclophosphamide,
vincristine, Adriamycin, and dexamethasone).
93K.N. Manola et al. / Cancer Genetics and Cytogenetics 187 (2008) 85e94
do not seem to contribute to the pathogenesis of leukemia,
but rather to the progression of the disease, possibly as
a causal event of leukemic transformation.
In conclusion, to the best of our knowledge, regarding
hematologic malignancies, this study presents the first case
of JT associated with AML-M1, the first case of JT involv-
ing 13q as a donor chromosome, and the first report of JT
involving a segment of 11q as a donor chromosome, result-
ing in six copies of the MLL gene. Moreover, our investiga-
tion suggests that JT may not contribute to the
pathogenesis, but rather to the progression, of the disease,
and it demonstrates that chromosome band 1q10 as a break-
point of the donor chromosome 1q is also implicated in
AML, not only in multiple myeloma as it has been known
until now.
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