jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving...

Jumping Translocations of Chromosome 1q in Multiple Myeloma: Evidencefor 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 clini-

cal specimens and cell lines involves aberrations of chromo-

some 1. Unbalanced translocations and duplications involv-

ing all or part of the whole long arm of chromosome 1

presumably occur as secondary aberrations and are associ-

ated with tumor progression and advanced disease. Unfortu-

nately, 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 karyo-

types. Recurring whole-arm translocations of 1q involved

chromosomes 5,8,12,14,15,16,17,19,21, and 22. A newly delin-

eated 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 acrocen-

tric chromosomes have also been identified, in-

cluding 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 re-

gions 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 decon-

densed 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 indi-

rectly provides a proliferative advantage.

r 1998 by The American Society of Hematology.

CHROMOSOME 1 aberrations are very common in mosthematologic malignancies and constitute the most com-

mon structural aberration in multiple myeloma (MM). Up to40% of patients with abnormal cytogenetics show chromosome1 rearrangements,1 which are the most common secondaryfindings in the complex karyotypes of MM.1-5 To date nodistinct clinical and prognostic features have been associatedwith extra copies of 1q, whereas aberrations involving chromo-somes 13 and 11q are associated with a poor prognosis inMM.6,7 Little is known about the progression of nonrandomsecondary chromosome events involving chromosome 1. Dupli-cations of all or part of 1q and whole-arm translocations of 1qare widely reported in neoplasia, but the origin of these majorgenomic rearrangements remains obscure. Extra copies of 1qcan occur as translocated unbalanced derivative chromosomes,isochromosomes, or ‘‘jumping translocations’’; however, theessential genetic characteristic is the same, resulting in partialtrisomies for the 1q segment.8-12

Whole-arm translocations of 1q become jumping transloca-tions when the 1q segment moves (jumps) around the karyotypeto more than one nonhomologous chromosome.

The cytogenetic changes associated with extra copies of 1qhave been attributed in part to cytotoxic treatments and in part

to the natural evolution of disease progression. Aberrations inthe centromeric regions of chromosomes can result in chromo-some instability, which can lead to a generalized breakdown innormal chromosome segregation, resulting in nondisjunction orunbalanced translocations during mitosis. The extra copies of1q present in B-cell acute lymphoblastic leukemia and manyadvanced neoplasias may confer a proliferative advantage.13

Although present in a wide variety of tumors, the movement ofchromosome 1q to one or more nonhomologous chromosomesand the resulting increase in copy number appear to be a specialtype of chromosome instability, because it has been reportedonly in a small fraction of patients with any given malignancyas jumping translocations. Unfortunately, the exact mechanismsby which whole chromosome arms separate and rejoin withother centromeres, telomeres, or interstitial sites is unknown.

We have analyzed chromosome 1 aberrations in 158 patientswith abnormal karyotypes and have found a subset of patientswith evidence of nonrandom whole-arm 1q aberrations. Theobservation that extra copies of 1q occurred in patients with thedecondensation of centromeric heterochromatin prompted anexpanded study of this group. The decondensation of the centro-meric heterochromatin of 1q suggests that hypomethylation ofthis region may play a role in the somatic pairing, fragility, andformation of triradial configurations involving the long arm ofchromosome 1. These events may be the precursors to thesubsequent jumping translocations found in some patients. Thestriking similarity between chromosome 1q aberrations in MMpatients and those with high-grade lymphomas suggests the pos-sibility of a common mechanism in a number of malignancies.

MATERIALS AND METHODS

Bone marrow of MM patients was processed for chromosome studiesas previously described.4 Twenty cells were studied in each case forroutine analysis. An abnormal clone was identified as two or moremetaphases displaying either the same structural abnormality or thesame extra chromosome or at least three cells with the same missingchromosome. Aberrations were designated according to ISCN.14

From the Departments of Pathology and Medicine, Arkansas CancerReseach Center, University of Arkansas for Medical Sciences; and theCytogenetics 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 pagecharge payment. This article must therefore be hereby marked‘‘adver-tisement’’ in accordance with 18 U.S.C. section 1734 solely to indicatethis fact.

r 1998 by The American Society of Hematology.0006-4971/98/9105-0026$3.00/0

1732 Blood, Vol 91, No 5 (March 1), 1998: pp 1732-1741

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RESULTS

Complete karyotype designations are provided in Table 1.These data represent a subset of cytogenetic findings in a groupof 427 MM patients previously reported.5 To briefly summarizethis patient population, 187 patients (44%) had normal, 158 hadabnormal (37%), and 82 had inevaluable karyotypes (19%).Within the subset of 158 patients with abnormal karyotypes, 50patients (32%) showed aberrations of all or part of 1q in themyeloma clone. These aberrations thus constituted the mostcommon recurring secondary abnormalities in our MM patients.Unbalanced whole-arm translocations were found in 26 pa-tients, whereas jumping translocations where the 1q wasobserved on more than one nonhomologous chromosome werefound in 10 patients (Nos. 1,2,3,4,8,9,14,17,22,36).

In decreasing order of frequency, 1q was translocated to15pter in 10 patients (Fig 1A), 22pter in 6 patients, and to 13pterand 21pter in 3 patients each. One 1q was translocated to 21qterin 3 patients. Translocations to nonacrocentric chromosomesincluded 1q to 19qter in 5 patients, to 19pter in 2 patients, to12qter in 3 patients (Fig 1B), to 8pter in 3 patients (Fig 1C), to9pter in 2 patients, and to 17qter in 2 patients (Fig 1E).Whole-arm centromere to centromere translocations occurredmost frequently between 16p and 1q in 9 patients.

The association of centromeric decondensation, separation,and subsequent jumping 1q is illustrated in detail by partialkaryotypes of nine cells each from three different patients.Patient No. 3 shows the jumping of 1q to 17q and subsequentlyto 7q (Fig 2A to I). The instability of chromosome 1 isassociated with partial duplications but also with decondensedchromosomes 1 crossed at the centromere (Fig 2A to C). Thechromosome crossovers in the decondensed centromeric re-gions suggest somatic association or pairing of centromericsequences. Even the der(17)t(1;17)(q10;q25) fusion chromo-some is involved in crossovers with the chromosomes 1 at thecentromere, which also suggests somatic pairing of the centro-meric 1q sequences between the chromosomes (Fig 2D and E).In some cells extreme decondensation of both chromosomes 1and crossing over shows the fragility of these configurations(Fig 2F).

Patient No. 22 (Fig 3A to I) shows the sequence of eventsleading to the der(19)t(1;19)(q10;p13) with the 1q jumping tothe telomere of the short arm of chromosome 19. First there isthe decondensation of 1qh and apparent separation of 1q insome cells (Fig 3A), whereas other cells show decondensationof two copies of chromosome 1 (Fig 3B). The association of theshort arm of 19 in the decondensed region of 1q can be clearlyseen (Fig 3C), as can the association of 19p with an extra copyof 1q while still in the decondensed regions of a triradialconfiguration of 1q (Fig 3D). The best illustration of a triradial 1configuration and the association of 19p is shown in Fig 3E.This cell appears to show the formation of an extra copy of 1qfrom the triradial and the initial fusion of 19p with the extracopy of 1q. This type of triradial configuration, which shows anapparent endoreduplication of 1q and association of the shortarm of chromosome 19 with 1q, indicates the likely origin ofder(19).

Patient No. 26 illustrates centromeric instability not only inchromosome 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. Thispatient showed centromeric decondensation and fragility (Fig4A to C), and many cells showed the crossing over of theder(19) with a decondensed chromosome 1, again suggestingsomatic pairing of centromeric 1q sequences (Fig 4D to H).

DISCUSSION

The primary numerical chromosome aberrations seen in MMkaryotypes apparently evolve over an extended period of timeas a subclinical phenomenon. In later stages of progressiveMM, cytogenetic evolution takes place, resulting in secondarychromosomal aberrations commonly involving chromosome 1.Structural aberrations of both arms involving reciprocal translo-cations are the most common findings. However, a special typeof whole-arm or jumping translocation somehow including anextra copy of 1q and its subsequent movement to anotherchromosome creates a partial trisomy for the whole long arm.Whole-arm translocations of 1q are different from jumpingtranslocations because in jumping translocations the 1q segmentbecomes unstable and moves (jumps) around the karyotype tomore than one nonhomologous chromosome. Trisomy for thelong arm of chromosome 1 is common in many types ofcancer15-18 and has been reported previously in leukemias andlymphomas showing multiple telomeric associations with differ-ent chromosomes.13,19-30Experimental evidence has shown thatdup 1q might be a secondary aberration associated with diseaseprogression26; however, they may also be primary aberrations insome cases.27 The correlation of trisomy for 1q with theprogression of malignancy has been correlated with the meta-static potential in colon and renal cell carcinomas, including theinvolvement of the SKI oncogene located at 1q21.31,32

The derivative (der) chromosomes we report have beenreported previously, with the exception of the der(5)t(1;5)(q10;q15) in the present study. The der(5) was found only inconjunction with other 1q aberrations and thus may constitute afurther unique step in the secondary evolution of the MMkaryotype. The recurring der(15)t(1;15)(q10;q10) in this reportis a rare but nonrandom change also associated with myelodys-plastic syndrome and myeloproliferative disorders. This aberra-tion has been reported as the sole aberration in most pa-tients.33,34 The der(16)t(1;16)(q10;p10) has been reported in awide variety of malignancies, including breast cancer, Ewing’ssarcomas, and Wilms’ tumors. This aberration has also beenreported as the sole aberration in some cases, but as a secondaryaberration in most patients.35-38 This whole-arm translocationhas been confirmed by fluorescence in situ hybridization usingprobes reacting with alphoid and classic satellite DNA.39 It maybe that the probability of recombination of these centromericrepeats is favored by the sequence homology shared in theregions corresponding to the t(1;16) exchange points. Thecentromeric regions of chromosomes 1,9,16 and Y containsatellite III DNA consensus sequences largely consisting of(GGAAT)n repeats and small clusters of satellite III DNAinterspersed among the alpha-satellite DNA.40 Guanine-richmotifs, such as telomere sequences (TTAGGG)n, adopt highlystable intra-strand and inter-strand duplexes and possibly tetra-plex structures that may favor recombination in this region.41,42

It has further been suggested that tetra-strand DNA has afunction related to nonhomologous recombination, telomere-

CHROMOSOME INSTABILITY IN MULTIPLE MYELOMA 1733




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


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]


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]


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)

1734 SAWYER ET AL




Table 1. Summary of Cytogenetic Findings (Cont’d)


17 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]


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]


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


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]


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]


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]


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)





telomere recombination, and immunoglobulin switch recombi-nation.42

Jumping translocations involving multiple chromosomes area rare phenomenon, the mechanisms of which remain obscure.

However, the types of chromosome 1 centromeric decondensa-tion observed in our patients appear to be similar and reminis-cent of changes observed in cells treated with the hypomethylat-ing agent 5-azacytidine.43,44This suggests that undermethylation

Table 1. Summary of Cytogenetic Findings (Cont’d)



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]


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]

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.

1736 SAWYER ET AL




is associated with the decondensation of the heterochromaticregions. Hypomethylation could be induced as a side effect ofcytotoxic therapy, have a viral association, or be part of anunknown process associated with tumor progression.

A viral origin for jumping translocations and juxta-centromeric fragility in neoplasia has been suggested.19 It isknown that gene products of certain DNA cancer viruses(SV-40, human papilloma virus, and adenovirus) can altercellular proteins and affect cell-cycle checkpoints, therebyinducing karyotype instability.45 A variety of chromosomeaberrations, including telomeric associations, dicentric chromo-somes, and aneuploidy, have been induced in human fibroblastsby the SV-40 virus,46-48 as have jumping translocations.48,49Analternative explanation to viral induction could be that, follow-ing DNA duplication, the hypomethylated decondensed state ofthe paracentromeric heterochromatic regions of homologouschromosomes preserves the interphase somatic pairing andaccounts for the multiradial associations observed at meta-phase.50 The persistent somatic pairing could result in multi-branched chromosomes of varying sizes from duplications of 1qoccurring in these cells. In fact, azacytidine-treated cells showuncoiling and somatic associations and indicate molecular

exchanges between classical satellite-containing regions inhomologous and nonhomologous chromosomes.51,52

As there are several possible mechanisms involved in jump-ing translocations, our findings suggest that a number ofchromosomal landmarks may be associated with the process of‘‘jumping copies of 1q.’’ In our patients we found recurrentcentromeric decondensations and centromeric separations assigns of hypomethylation of the centromeric heterochromatin.The duplication of part of 1q is often seen in the same patientswho subsequently show duplications of the entire 1q. Decon-densed chromosomes 1 frequently cross over apparently as aresult of sequence homology (somatic pairing) in the stretchedregions (Figs 2 to 4). Triradials as seen in patient No. 22 (Fig3E) are rare events and are believed to arise from the partialendoreduplication of a chromosome arm.53 Interestingly, thecombination of hypomethylation and the appearance of triradialchromosome configurations as observed here have been re-ported elsewhere in both neoplastic and non-neoplastic disor-ders. A rare pediatric immunodeficiency syndrome (ICF syn-drome) shows the most striking array of triradial and multiradialchromosomes.54These patients show an embryonic-like methyl-ation pattern of classical satellite DNA and multibranched 1q in

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).





peripheral blood lymphocytes.55 In neoplastic disorders, decon-densation of 1q and jumping translocations have been reportedin an HIV-related non-Hodgkin’s lymphoma.30 Although thefactors involved in the induction of the centromeric decondensa-tion may be different, and the resulting clonal expansion isdifferent, the striking similarity of chromosome triradials isintriguing.

The hypothesized model of the clonal evolution of tumor-cellpopulations suggests that during the cytogenetic progression ofmalignancy acquired genetic lability permits the stepwiseselection of variant subclones.56 During this evolution tumor-cell populations emerge that may or may not be viable. Nearlyall variants are eliminated, but occasionally one has a selectiveadvantage and becomes the predominant subpopulation. It islikely that hypomethylation is induced by a variety of mecha-nisms. However, hypomethylation appears to be the criticalevent associated with the decondensation and subsequentinstability of the classical satellite sequences associated with thepericentromeric heterochromatin of chromosome 1 (Fig 2). Thisdecondensation in some patients is apparently followed by

duplication of 1q regions adjacent to the heterochromatin ofchromosome 1 resulting in what presents as triradial chromo-somes 1q (Fig 3). These configurations may result from somaticpairings of chromosome 1 with the resulting loss of 1p and thesubsequent translocation or jumping of the 1q to other chromo-somes. The finding of triradial chromosomes in patients isextremely rare because these configurations are unstable andprobably lost as micronuclei. Apparently, in some patients,these configurations do not evolve, whereas in other patients theentanglement of other chromosomes in the decondensed hetero-chromatic regions adjacent to an extra copy of 1q may causechromosome arm exchanges (Fig 4). The highly decondensedheterochromatin may provide an opportunity for the fusion ofthis chromosome segment to other chromosomes because thehypomethylated segments may favor recombination. Once the1q has translocated to another chromosome it is likely the onlystable chromosome change to survive from the transitional(unstable) triradial. Our data suggest a speculative model forheterochromatin decondensation in the dynamics of 1q translo-cations (Fig 5).

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).

1738 SAWYER ET AL




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.




The equilibrium between proliferation and programmed celldeath in MM cells is believed to be controlled in part bycytokines. In this respect, growth control of MM cells may beaffected by increased gene dosage related to duplications of partor all of the long arm. The observation of extra copies of 1qsuggests several possibilities for low-level gene amplificationindicated by the presence of genes related to MM biology. Theinterleukin-6 (IL-6) signaling pathway may possibly be affectedby the amplification of the 1q21 region, which is the site ofIL-6RA.57 Other genes of interest in this region includeC-reactive protein (CRP) and amyloid P component (APCS),both localized to 1q21-23,58 and pre–B-cell leukemia transcrip-tion factor 1 (PBX1) at 1q23.59

Chromosome aberrations often have diagnostic and prognos-tic significance. The roles played by cytotoxic drugs, ionizingradiation, or oncogenic viruses in the evolution of secondarychromosomal aberrations in MM are still far from clear. Itseems likely that these factors interact with the cell genome in avariety of ways to bring about at least a gene dosage effectcaused by the extra copies of 1q. The evolution of centromericinstability appears to be the precursor for subsequent telomericfusions and jumping translocations in some patients. Deconden-sation and stretching of centromeric heterochromatin is associ-ated with the persistence of somatic pairing, multibranchedchromosome arms, whole-arm deletion, duplication, isochromo-somes, and centromeric fragility.52,53,60 The progression ofcentromeric destabilization in these patients, from simpleheterochromatic decondensation to subsequent multibranchingand jumping translocations, shows a sequence of events in itsprogression. We speculate that hypomethylation-induced peri-centromeric heterochromatin decondensation is an initiatingevent.

ACKNOWLEDGMENT

We gratefully acknowledge the expert technical assistance of cytoge-netic technologists Eddie Thomas, Charles Swanson, Linda Goosen,Mamie Crowson, Gael Sammartino, Emmett Jones, and Janet Lukacs.

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1998 91: 1732-1741

Jeffrey R. Sawyer, Guido Tricot, Sandy Mattox, Sundar Jagannath and Bart Barlogie Heterochromatinfor a Mechanism Involving Decondensation of Pericentromeric Jumping Translocations of Chromosome 1q in Multiple Myeloma: Evidence

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