Leukemia (1999) 13, 1975–1981  1999 Stockton Press All rights reserved 0887-6924/99 $15.00 http://www.stockton-press.co.uk/leu Fluorescence in situ hybridization analysis of 1 abnormalities in hematopoietic disorders: rearrangements of DNA satellite II and new recurrent translocations M Busson-Le Coniat1, F Salomon-Nguyen1, N Dastugue2, O Maarek3, M Lafage-Pochitaloff4, M-J Mozziconacci4, L Baranger5, F Brizard6, I Radford7, M Jeanpierre8, OA Bernard1 and R Berger1

1INSERM U434 and CNRS SD401 No. 434, CEPH, Institut de Ge´ne´tique Mole´culaire, Paris; 2Ge´ne´tique des He´mopathies, CHU Toulouse- Hoˆpital de Purpan, Toulouse; 3Laboratoire Central d’He´matologie, Hoˆpital Saint-Louis, Paris; 4Cytoge´ne´tique, Institut Paoli-Calmettes and INSERM U119, Marseille; 5Service de Ge´ne´tique, CHU, Angers; 6Laboratoire Central d’He´matologie, CHU de Poitiers, Poitiers; 7Unite´ de Cytoge´ne´tique He´matologique, Hoˆpital Necker-Enfants Malades, Paris; and 8Service de Biochimie et Ge´ne´tique Mole´culaire, Hoˆpital Cochin- Maternite´s, Paris, France

Using fluorescence in situ hybridization analysis, breakpoints in 36 patients with various hematopoietic malignancies. It involving the long arm of (1q) were localized in seems to us that the demonstration of the recurrence of some 36 patients with various hematopoietic disorders and rearrangements of the proximal part of 1q, as ascertained with chromosomal breakpoints with banding and FISH techniques banding techniques. The breakpoint was localized within the precedes any research on the mechanisms resulting in the satellite II (sat II) domain in 14 patients with various abnormali- rearrangements, as well as their molecular consequences. ties, between the sat II domain and the BCL9 in eight, between the BCL9 and ARNT loci in two, between sat II and ARNT in two others, and distal to ARNT in seven. A dicentric chromosome 1 was present in two patients. A high incidence Materials and methods of heterochromatin heteromorphism of chromosome 1 was present in this series. Two recurrent translocations were ident- ified, t(1;2)(q12;q37) in three patients suffering from three dif- Patients ferent acute leukemia subtypes, and t(1;16)(q12;q24) in two patients with different diseases. Two patients had jumping The 36 patients with hematopoietic disorders included in the translocations. Most of the rearrangements of 1q were second- present work were selected on the basis of the presence of 1q ary abnormalities, included in complex karyotypes. The roles of methylation, interactions with the interfering with rearrangements as detected by banding techniques. They were heterochromatin and possible silencing due to hetero- initially studied in different French centers (Hoˆpital Saint Louis, chromatin rearrangements are discussed. Paris;U301and434INSERM,Paris;HopitalNecker-Enfants Keywords: chromosome 1; hematopoietic disorders; satellite DNA; Malades, Paris; CHU de Poitiers; CHU d’Angers; CHU de Toul- recurrent translocation ouse;InstitutPaoli-Calmettes,Marseille).Thepatientswere examined for various hematopoietic malignancies mainly at diagnosis, and some in relapse, as summarized in Table 1. Introduction FISH studies were performed using probes covering repeated sequences specific to the chromosome 1 centromeric area and Rearrangements of the long arm of chromosome 1 (1q) have YAC probes covering loci located in the 1q proximal regions. been recognized to occur in various hematopoietic malignant These probes were D1Z5 (chromosome 1-specific alpha satel- disorders as early as banding techniques were applied to their lite; Appligene Oncor, Montreuil-sous-bois, France), CEP1 study.1,2 Translocations, complete and partial trisomies, and (chromosome 1-specific satellite II–III; Vysis, Voisin le Breton- deletions involving 1q are indeed commonly present in vari- neux, France), CB2 (chromosome 1-specific satellite II; M Jean- ous leukemia subtypes, myeloproliferative disorders, myelo- pierre, Service de Biochimie, Hoˆpital Cochin, Paris), YAC dysplastic syndromes, and lymphoid proliferations.3 They may 882b3 covering the gene BCL9,5 andBAC904E5coveringthe occur both as ‘primary’ or ‘secondary’ chromosomal abnor- gene ARNT (CEPH, Paris, France). Preliminary experiments malities in different patients. The breakpoints are variable and showed the following order of the loci on chromosome 1: cen- several affect identified gene loci. The most frequent recurrent tromere-BCL9-ARNT-AF1q-PBX1-telomere. The BCL9 and translocation identified to date is t(1;19)(q23;p13) in acute ARNT loci were chosen because both were located within lymphoblastic leukemia resulting in E2A-PBX1 fusion gene.3 band 1q21 and because the aim of this study was mainly to Translocation t(1;11)(q21;q23) fuses the AF1q and MLL identify rearrangements closely located to the chromosome 1 ,3 t(1;12)(q21;p13) fuses ARNT and ETV6/TEL4 (and heterochromatin. Telomeric probes were also used: cosmid unpublished data), and t(1;14)(q21;q32) involves BCL9 and probes corresponding to 2q and 16q (L Kearney, MRC, Molecu- IGH.5 Centric and pericentric chromosome rearrangements lar Haematology, Oxford, UK), and YAC 75 corresponding to have been recently claimed to occur more frequently than 2q (D Le Paslier, CEPH, Paris, France). hitherto admitted.6 To investigate more precisely for the poss- Techniques were performed as previously described6 or fol- ible recurrence of breakpoint localizations, we have extended lowing the instructions of the manufacturers for the commer- the cytogenetic and FISH (fluorescence in situ hybridization) cial probes. The metaphase were coun- analysis of rearrangements of the long arm of chromosome 1 terstained by propidium iodide in monocolor and DAPI in bicolor FISH studies. The presence of asymmetry of heterochromatin area (length, partial inversion) between the two homologuous chromo- Correspondence: R Berger, INSERM U 434, Institut de Ge´ne´tique Mole´culaire, 27 rue Juliette Dodu, 75010 Paris, France; Fax: 33 1 somes 1 defining heterochromatin heteromorphism was sys- 5372 5192 tematically noted in reference to its possible significance as a Received 15 June 1999; accepted 4 August 1999 constitutional factor favoring chromosomal rearrangements. Satellite II rearrangements in leukemia M Busson-Le Coniat et al 1976 Table 1 Patients with 1q rearrangements: diagnosis and karyotypes

Patient Sex/Age Diagnosis Status Karyotype

1 F/76 AML-M0 D 46,XX,der(2)t(1;2)(q12;q35–37),t(9;22)(q34;q11)/47,idem,+der(22)t(9;22)[2]/48,idem,+15/46,XX, der(2),add(7)(q35),t(9;22)[2]/46,XX[2] 2 M/81 AML-M4 D 45,X,−Y[10]/46,X,−Y,t(1;2)(q12;q37),+8[12]/46,XY,t(1;16)(12;q24),+8[5]/46,X,−Y,t(1;19)(q12;q13)[3] (Blood:45,X,−Y[3]/47,XY,+8[3]/46,X,−Y,t(1;2)(q12;q37),+8[3]/46,X,−Y,t(1;19)(q12;q13),+8[2]/46,X,−Y, +8,add(11)(p15)[2]) 3 M/65 AML-M R 46,XY,t(9;22)(q34;q11)[8]/46,idem,der(7)t(1;7)(q12–21;q31)[10]/46,XY[10] 4 F/1 AML-M5 D 46,X,−X,+der(X)t(X;1)(q28;q12)[23]/46,XX[6] 5 M/65 PV D 46,XY,der(14)t(1;14)(q11;p11)[22] 6 F/7 ALL D 56,XXXX,t(2;16)(p12;q12),+4,+5,+6,+10,+18,der(20)t(1;20)(q12;q13),+21×2,+min[12]/46,XX[15] 7 F/65 ALL D 45,XX,−7,t(9;22)(q34;q11),der(12)t(1;12)(q21–22;q24)[18]/45,XX,−7,t(9;22),der(11)t(1;11)(q21–22;p15) [2]/45,XX,−7,t(9;22),der(21)t(1;21)(q21–22;p11)[2]/45,XX,−7,t(9;22),der(1)(t(1;1)(p36;q21–22)[1]/46,XX[2] 8 M/69 ALL-L1 D 46,XX,der(2)t(1;2)(q12–21;q37),del(7)(q21q31),t(9;22)(q34;q11)[5]/46,idem,add(6)(p25),t(17;19) (q11–12;p13.3),−19[13] 9 M/11 ALL-L3 D 46,XY,dupdir(1)(q12q44),t(8;14)(q24;q32)[30] 10 M/58 NHL,B D 53,XXY,dup(1)(q12q24),+5,+10,+12,+13,+22,der(19)t(1;19)(q12;p13)[8]/46,XY[8] 11 M/ NHL,B R 51,XY,del(1)(q12),+der(1)t(1;1)q12;q12),+2,del(4)(q21q33),+del(6)(q24),add(14)(q32),+15,+21[cp12] /46,XY[14] 12 M/49 NHL,B D 48,XY,+der(6)t(1;6)(q12;p25)×2,+7,add(14)(q32)[c7]/46,XY,t(8;14)(q24;q32)[3]/46,XY[9] 13 F/79 CLL t 46,XX,dup(1)(q12q44),t(9;14)(p12;q32),dup(12)(q13q24)[19]/N[6] 14 F/9 FA D 46,XX,der(16)t(1;16)(q12;q24)[17]/46,XX[14] 15a M/71 AML-M4 D 46,XY,der(6)t(1;6)(q21;p21–22)[34] 16 F/5 ALL D 57,XX,dup(1)(q12q44)+4,+6,+7,+8,+11,+14,+17,+18,+21,+21,+22[9]/58,idem,+3[10]/46,XX[3] 17 M/5 ALL D 47,XY,der(2)t(1;2)(q12;p23),t(5;11)(q31;q23),+8[22]/46,XY,idem,t(10;11)?(p12;q14)[2] 18 M/9 ALL-L3 D 46,XY,t(1;22)(p11;p11),t(8;14)(q24;q32)[18]/46,XY,dup(1)(q11q44)[7]/46,XY[1] 19 F/15 BL D 46,XX,der(6)t(1;6)(q21;q23),t(8;14)(q24;q32)[13]/46,XX[108] 20 F/28 NHL D 46,XX,add(1)(q21),del(7)(q35),del(9)(p12),add(14)(q32)[6]/47,idem,+3[17]/46,XX,add(1)(q21),del(7) (q35)[1]/47,XX,+del(7)(q35),del(9)(p12),add(14)(q32) [2]/46,XX[1] 21 F/52 NHL R 48,XX,add(2)(q22?),der(4)t(1;4)(q12;p16),add(5)(q21),add(6)(q14?),?del(10)(p11p13),dup(12) (q12q21),t(14;18)(q32;q21),+der(18)t(14;18),+mar[cp37] 22 M/76 HD 46,XY,−18,der(21)t(1;21)(q21–22;q22),+21[3]/46,XY,add(5)(p14),der(21)t(1;21)[3]/46,XY,der(1)t(1;6) (p36,q12–21),del(6)(q21–22)[1]/47,XY,del(1)(p32),+1,del(6)(q21–22),−8,+21[2]/45,XY,del(1)(p32), +dert(1;6)del(6),−13,−18[2]/46,XY[12] 23 M/22 AML-M1 D 46,XY,der(16)t(1;16)(q21;q24)[20] 24b M/62 AML D 46,X,t(Y;1)(p11;q21)[24] 25 M/60 CML-CP D 46,XY,t(1;17)(q12;q25),t(9;22)(q34;q11)[20] 26 F/18 ALL-B D 46,XX,der(19)t(1;19)(q23;p13),der(10)t(1;10)(q21;q26)[2]/46,XX,idem,der(17)t(1;17)(q21;p13)[2]/46, XX,der(19),der(10),t(1;9)(q21;p24)[1]/46,XX,der(19),der(13)t(1;13)(q21;p11)[1]/46,XX,[20] 27 M/8 BL D 46,XY,dup(1)(q12q41),del(6)(q14q23),t(8;14)(q24;q32)[21] 28 M/70 AML-M1 D 46,X,−Y,add(1)(q22),del(5)(q23q34),−7,+8,+8,add(12)(p13),−16,+min[20] 29 F/40 AML-M3 D 46,XX,inv(1)(p21p34),t(1;12)(q12;q22),t(8;9)(q22;q31),der(12)(12p13–12q22::1q44–1q12),t(3;6) (p26;p12),t(15;17)(q12;q11)[22] 30 M/59 AML-M4 D 46,XY,t(1;22)(q21–22;q11–12)[22]/46,XY[2] 31 M/69 RAEBt D 44–48,XY,−1,+der(1)t(1;?),−5,i(8)(q10),add(11)(p15),der(12)t(12;?),+mar[cp26]/46,XY[3] 32 F/74 RAEBt D 46,XX,del(5)(q1?)/45–46,XX,del(1)(q23),del(5)(q1?),add(10)(p15),del(12)(p1?),−16,i(17)(q10),+mar1 [cp12]/N[12] 33 F/63 NHL D 44–45,X,−X,t(1;8)(q22;q24),del(6)(q15q23),−9,t(11;14)(q13;q32),−13,−21,+mar1,+mar2,+mar3[20] /44–45,idem,der(1)[4] 34 F/63 CLL 46,XX,del(1)(q21q25),add(7)(q36),del(10(q22)[2]/46,idem,del(11)(q22q23)[3]/47,idem,+21[1]/46,XX, del(11)(q22q23)[5]/46,XX,t(1;4)(q32;q28),del(11)(q22q23)[1]/46,XX[11] 35 F/22 ALL-L2,T D 49,X,t(X;4)(q25;q3),t(1;9)(q11–12;q11–12)−5,+8,?del(10)(q25q26),add(12)(q11),+17,?del(17)(p11), +der(?)t(?12)(?;q13)×2,+mar[14]/46,XX[2] 36 M/64 NHL,T R 41–45,XY,t(1;7)(q21;q36),del(2)(q32),add(3)(p23),t(4;6)(q21;q26),−10,−13,add(14)(q32),−15,−21[cp21]

AML-M0, M1, M3, M4, M5, acute myeloblastic leukemia; M0, M1, M3, M4, M5 in the French–British–American (FAB) nomenclature; ALL, acute lymphoblastic leukemia; L1, L3 in the FAB nomenclature; BL, Burkitt lymphoma; CLL, chronic lymploid leukemia; CML-CP, chronic myeloid leukemia, chronic phase; FA, Fanconi anemia; HD, Hodgkin disease; MPD, myeloproliferative disorder; MDS, myelodysplastic syndrome; NHL, B, NHL, T, non-Hodgkin lymphoma, B-cell, T-cell; PV, polycythemia vera; RAEBt, refractory anemia with excess of blasts in transformation; D at diagnosis; R, in relapse; t, treated. aAML-M4 at diagnosis of blastic phase of MPD or MDS. bAML at diagnosis of blastic phase of MPD.

Results Localization of the chromosomal breakpoints on chromosome 1 Chromosome 1 rearrangements were variable in the different patients. They were identified as translocations, deletions, or The localization of the chromosome 1 breakpoints was refined partial duplications by analysis of banded karyotypes. In most by FISH analysis in every case. They were distributed within of the patients, they were part of complex karyotypes with several intervals between 1cen and 1q23 (Table 2). more than three different abnormalities. The breakpoint was located within the satellite II domain Satellite II rearrangements in leukemia M Busson-Le Coniat et al 1977 Table 2 Result of FISH experiments in patients with 1q rearrangements

Patient No. Hybridization signal of probes on the rearranged Localization of No. 1 hetero- abnormality chromosome region the breakpoint chromatin on 1q asymmetry DIZ5 (alpha CB2 CEP1 Yac 882b3 BAC 904E5 satellite) (satellite II) Satellite II–III (BCL9) (ARNT)

1 AML-M0 der(2)t(1;2)(q12;q35–37) −+ ++ within sat II − 2 AML-M4 der(2)t(1;2)(q22;q37) −+ ++ within sat II + t(1;16)(q12;q37) −+ within sat II t(1;19)(q12;q13) −+ within sat II 3 AML-M4 (relapse) der(7)t(1;7)(q12–21;q31) −+ ++ within sat II − 4 AML-M5 der(X)t(X;1)(q28;q12) −+ + within sat II + 5PV der(14)t(1;14)(q12;p13) −+ ++ within sat II + 6 ALL der(20)t(1;20)(q12;q13) −+ ++ within sat II + 7 ALL der(12)t(1;12)(q21–22;q24) −+ ++ within sat II − 8 ALL-L1 der(2)t(1;2)(q12–21;q37) −+ ++ within sat II + 9 ALL-L3 dup dir(1)(q21q44) −+ within sat II + 10 NHL dup(1)(q12q24) −+ ++ within sat II − der(19)t(1;19)- +++ within sat II 11 NHL der(1)t(1;1)(q12;q12) −+ ++ within sat II + del(1)(q12) +− −−distal to alpha satellite 12 NHL der(6)t(1;6)(q12;p25) −+ ++ within sat II + 13 CLL dup(1)(q21q44) −+ ++ within sat II − 14 FA der(16)t(1;16) −+ ++ within sat II − 15 AML (MDS or MP −BP) der(6)t(1;6)(q21;p21–22) −−−++between cen and BCL9 + 16 ALL dup(1)(q12q44) −−−++between cen and BCL9 + 17 ALL der(2)t(1;2)(q12;p23) −−−++between cen and BCL9 + 18 ALL-L3 t(1;22)(p11;p11) −−−++between cen and BCL9 + 19 BL der(6)t(1;6)(q21;q21) −−−++between cen and BCL9 + 20 NHL add(1)(q21) −−−++between cen and BCL9 + 21 NHL der(4)t(1;4)(q12;p15) −−−++between cen and BCL− 22 NHL der(21)t(1;21)(q21;q22) −−−++between cen and BCL9 + der(1)t(1;6)(p36,q12–21) −−−++between cen and BCL9 der(1)t(1;?)(p32;?) +++++ 1p32 23 AML-M1 der(16)t(1;16)(21:q24) −− − + between BCL9 and ARNT −

or between the alphoid and satellite II domains in 14 patients three patients with different leukemias, AML-M0 in patient 1, (Nos 1–14, Table 2). The corresponding hematological dis- AML-M4 in patient 2 (Figure 1), and ALL-L1 in patient 8. The orders were heterogeneous. Five patients (Nos 3–5, 9, 14) had breakpoint on the rearranged chromosome 2 was distal to the simple karyotypes with translocations involving 1q, one had localization of YAC and/or cosmid probes specific its telo- a partial 1q duplication associated with the common Burkitt meric region, as shown by FISH experiments in the three leukemia translocation t(8;14) (No. 9) and the others had com- patients. Similarly, two der(16)t(1;16)(q12;q24) translocations plex chromosomal rearrangements. The same rearrangement, were detected. FISH using the 16q telomeric cosmid probe der(2)t(1;2)(q12;q37) resulting in trisomy 1q was present in showed a signal on the derivatives chromosomes 16 in the Satellite II rearrangements in leukemia M Busson-Le Coniat et al 1978 Table 2 Continued

Patient No. Hybridization signal of probes on the rearranged Localization of No. 1 abnormality chromosome region the breakpoint hetero- on 1q chromatin DIZ5 (alpha CB2 CEP1 Yac 882b3 BAC 904E5 asymmetry satellite) (satellite II) Satellite II–III (BCL9) (ARNT)

24 AML (MPD-BP) t(Y;1)(p11;q21)[24] −− −+between BCL9 and + ARNT 25 CML-CP der(17)t(1;17)(q21;q25) −− −+between BCL9 and + ARNT 26 ALL B der(10)t(1;10)(q21;q26) −− ND + between cen and − ARNT der(13)t(1;13)(q21;p11) −− ND + between cen and ARNT der(17)t(1;17)(q21;p13) der19)t(1;19)(q23;p13) 27 BL dup(1)(q12q41) −− ND + between cen and + ARNT 28 AML-M1 add(1)(q22) ++ ++telomeric to ARNT + 29 AML-M3 t(1;12)(q12;q22) ++ ++telomeric to ARNT − 30 AML-M4 t(1;22)(q21–22;q11–12) ++ ++telomeric to ARNT − 31 RAEBT 69a der(1)t(1;?)=t(1;21) ++ ++telomeric to ARNT + 32 RAEBT del(1)(q) ++ ++telomeric to ARNT + del(12p) t(1;12) with loss of YAC 936e2 signal 33 NHL +++ +telomeric to ARNT + 34 CLL del(1)(q21q25) ++ ++telomeric to ARNT −

Dicentrics 35 ALL-L2 T t(1;9)(q11–12;q11–12) ++ dicentric, breakpoint on 1p 36 NHL der(7)t(1;7)(q21;q36) + dicentric, breakpoint on 1p

two patients. The breakpoints should consequently be located with AML-M1, another with myeloproliferative disorder in telomeric to these probes. In addition, a jumping translocation blastic transformation, and the third with chronic myelocytic involving 1q12, with t(1;2), t(1;16), and t(1;19) was detected leukemia in chronic phase. Two had simple translocations, in patient 2, and another possible jumping translocation with t(1;16) and t(Y;1) respectively, and the third t(1;17) in addition t(1;1), t(1;11), t(1;12), t(1;21) was found in patient 7. Chromo- to the t(9;22) tranlocation. some 1 heterochromatin asymmetry (heteromorphism) was The breakpoints were located between the centromeric area present in eight out of 14 patients of this subgroup. and the ARNT locus in two other patients (Nos 26 and 27), The breakpoints were localized between the satellite II–III one with ALL and the other with Burkitt lymphoma, both with pericentromeric domain of chromosome 1 and the BCL9 complex karyotypes. A more precise localization of the break- locus (band 1q21) in eight patients (Nos 15 to 22) with vari- point could not be done because of the shortage of material. ous disorders. It is noteworthy that seven had lymphoid The chromosome 1q breakpoint was found to be telomeric malignancies, ALL or non-Hodgkin malignant lymphoma to the ARNT locus in seven patients (Nos 28 to 34) with vari- (two with Burkitt-type proliferation). Six had complex kary- ous disorders. The rearranged chromosomal bands were 1q21, otypes, while the patient with myeloid disorder had t(1;6) as 1q22, and even 1q23 in one patient, as defined by banding the sole abnormality. Chromosome 1 heterochromatin heter- analysis, and it is well known that the distinction between omorphism was present in seven out of eight patients of 1q21 and 1q22 can be difficult in metaphases from patients this subgroup. with malignancies. Chromosome 1 heterochromatin hetero- The breakpoints were localized between the BCL9 and morphism was present in four out of the seven patients of ARNT loci on band 1q21 in three patients (Nos 23–25), one this subgroup. Satellite II rearrangements in leukemia M Busson-Le Coniat et al 1979 within 1q by FISH analysis. A previous study had indeed focused on the not uncommon occurrence of centromeric and pericentric rearrangements in hematopoietic malig- nancies, which could be difficult to ascertain without use of FISH techniques.6 The breakpoints were localized within the satellite II domain, or between the alpha satellite and satellite II–III domains of chromosome 1 in 14 out of 36 patients, and between the satellite II–III domains and the BCL9 locus in eight patients. Heteromorphism of chromosome 1 heterochromatin was present in 8/14 and 7/8 patients, respectively. Although no series of controls could be established because of the diversity of the recruitment of the patients (six centers), the proportion of patients with, vs those without heteromorphism seems to be high. Because of the variability of the frequency of hetero- morphism in different populations,7 the comparison of patients and controls remains to be carried out on more important series of individuals. Three patients with der(2)t(1;2)(q12;q37) and three different subtypes of leukemia were detected. The t(1;2)(q12;q37) trans- location appears to be a novel nonrandom chromosome abnormality of hematopoietic disorders. Although FISH experiments did not show hybridization of the 2q telomeric probes to the heterochromatin of chromosome 1, it is not possible to exclude the presence of homologous DNA repeated sequences on both chromosomes favoring the illegit- imate recombination resulting in t(1;2) translocation. Three patients had t(1;16) translocation, two with breakpoints in 1q12 involving heterochromatin, and one 1q21 and 16q24. In the two translocations t(1;16)(q12;q24), which could be studied with 16q telomeric probes, hybridization signals were present on the derivative 16 chromosomes, and the same question about the existence of DNA of 16q and heterochromatin of chromosome 1 should be addressed. It is worth noting that telomeric regions are frequent part- ners of 1q in the rearrangements of the present series of patients (Table 1). Homology between DNA sequences located in the vicinity of the chromosomal breakpoints could account for this observation. Jumping translocations may involve various chromo- somes.8 Some cases of jumping translocations with involve- ment of bands 1q11–q21 have been previously reported in various hematopoietic malignancies.9–15 In the two jumping translocations reported in the present study, the breakpoints Figure 1 Metaphase of patient 2: the arrow shows the der(2)t(1;2) were in heterochromatin, and the band 1q12 was the donor chromosome. (1c) Heterochromatin revealed with DAPI staining; (2c) in situ hybridization with the CB2 probe, chromosome 1 satellite 2- to several recipients. The mechanism of instability respon- specific. sible for these jumping translocations is still unknown. Abnormal methylation and viral interaction have been hypo- thesized without experimental proof. Recently a novel mem- brane gene, named JTB, at 1q21 has been found rearranged in a jumping translocation of an acute myelo- Two patients (Nos 35 and 36) had dicentric chromosomes, monocytic leukemia complicating a myelodysplastic syn- ascertained using chromosome-specific probes. One with drome with shortened telomeres.15,16 It is however too early NHL in relapse had dic(1;7), and the other with ALL-L2 of T to know if this rearrangement is casual or represents a more lineage dic(1;9). Only the first patient with dic(1;7) had general abnormality. chromosome 1 heterochromatin heteromorphism. Heteromorphism of heterochromatin was extensively stud- ied since the late seventies when Atkin17 suggested that it could be a constitutional marker for a high risk of malignant Discussion disease.18–20 Despite some discrepancies, different studies showed differences of the distribution of heteromorphism fre- A series of 36 patients with various hematologic disorders quencies between patients with malignancies and controls, and rearrangements of the proximal part of the long arm of with some variability among different malignancies. The chromosome 1 was collected from six cytogenetic labora- results of these studies were based upon statistical analyses tories in order to refine the localization of the breakpoints of series of patients. Because of the availability of molecular Satellite II rearrangements in leukemia M Busson-Le Coniat et al 1980 probes, the possible role of heteromorphism of heterochro- Acknowledgements matin as a factor predisposing to malignancy can now be reanalyzed at the molecular level. The analysis can conse- FS-N is recipient of a fellowship of the Ligue Nationale Contre quently be performed at the indidual level and not only at le Cancer. This work was in part supported by grants from the the population level as in the past. Association Contre le Cancer (ARC). Moreover, data on molecular structure and composition of heterochromatin suggest a hypothesis on the formation of chromosomal rearrangements, as well as their functional References consequences. As far as the production of rearrangements involving heterochromatin is concerned, several non-exclus- 1 Rowley JD. Abnormalities of chromosome 1 in myeloproliferative ive mechanisms can be hypothesized. disorders. Cancer 1975; 36: 1748–1757. 2 Rowley JD. Mapping of human chromosomal regions related to Abnormal pairing of heterochromatin between some dis- neoplasia: evidence from chromosomes 1 and 17. Proc Natl Acad tantly related sequences, although still controversial, can be Sci USA 1977; 74: 5729–5733. particularly invoked in patients with chromosome 1 heter- 3 Mitelman F, Mertens F, Johansson B. A breakpoint map of recur- ochromatin heteromorphism, which seems to be mainly rent chromosomal rearrangements in human neoplasia. Nat Genet related to different amounts of chromosome 1 DNA satel- 1997; 15: 417–474. 4 Berger R, Le Coniat M, Lacronique V, Daniel M-T, Lessard M, lite II. Berthou C, Marynen P, Bernard O. Chromosome abnormalities of The methylation status of the centromeric DNA of chromo- the short arm of chromosome 12 in hematopoietic malignancies: a some 1 could be altered in malignancies. 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