Twenty new cases of acute lymphoblastic leukemia (ALL) with the dicentric chromosome dic(9;20)(p11 13;q11) are presented. This chromosomal abnormality is ...
Leukemia (2000) 14, 241–246 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu
Monosomy 20 as a pointer to dicentric (9;20) in acute lymphoblastic leukemia R Clark1, S-A Byatt1, CF Bennett1, M Brama1, M Martineau1, AV Moorman1, K Roberts1, LM Secker-Walker1, S Richards2, OB Eden3, AH Goldstone4 and CJ Harrison1 1 Leukaemia Research Fund/United Kingdom Cancer Cytogenetics Group Karyotype Database in Acute Lymphoblastic Leukaemia, Department of Haematology, Royal Free and University College Medical School, London; 2Clinical Trial Service Unit and Epidemiological Studies Unit, Radcliffe Infirmary, Oxford; 3Academic Unit of Paediatric Oncology, Christie Hospital (NHS Trust), Manchester; and 4 Department of Haematology, University College Hospital, London, UK
Twenty new cases of acute lymphoblastic leukemia (ALL) with the dicentric chromosome dic(9;20)(p11苲13;q11) are presented. This chromosomal abnormality is difficult to identify from Gbanding alone. It masquerades as monosomy 20 and is only accurately identified by fluorescence in situ hybridization (FISH). Monosomy 20 was found in 59/2790 patients with successful karyotypes entered to the Leukaemia Research Fund/UK Cancer Cytogenetics Group Karyotype Database in ALL (LRF/UKCCG Karyotype Database). FISH revealed dic(9;20) in 20/25 cases with available material. Extra copies of chromosome 21 were found in 8 of the 20 cases. Patients were 14 females and six males, aged 1–32 years (median 4 years), with leukocyte counts of 2–536 (median 23) × 109/l and immunophenotypes of common or pre-B ALL (17 cases), T-ALL (one case) or unknown (two cases). Four patients relapsed at 2, 22, 28 and 47 months and two died at 49 and 63 months (median follow-up 37 months). FISH studies on the remaining five patients showed one with monosomy 20 and four with other rearrangements of the chromosome. This study has increased the number of reported cases of dic(9;20) from 17 to 37. It has identified dic(9;20) in one case of T-ALL and shows an association of this translocation with trisomy 21. Leukemia (2000) 14, 241–246. Keywords: acute lymphoblastic leukemia; dicentric translocation dic(9;20); fluorescence in situ hybridization (FISH); cytogenetics
probes for chromosomes 9 and 20 on cytogenetic preparations from 25 patients from whom material was available. Patients found to have dic(9;20) are compared with previously published cases to confirm dic(9;20) as a new chromosomal subgroup in ALL.
Materials and methods
Patients To date, the LRF/UKCCG Karyotype Database has 2790 successful karyotypes from patients with de novo ALL who have been entered into the UK Medical Research Council (MRC) treatment trials: MRC Infant Protocol for infants (0–1 year); UKALLXI and ALL 97 for children (1–14 years); and UKALLXII for adults (15–55 years). Monosomy 20 was identified by cytogenetics in 59 patients (2%) of whom 51 were children and eight were adults.
Cytogenetic studies Introduction The dicentric translocation, dic(9;20)(p11苲13;q11), was first reported as a new non-random chromosomal abnormality in patients with acute lymphoblastic leukemia (ALL) by Rieder et al1 in 1995. Two further reports have demonstrated the same chromosomal change,2,3 bringing the total number of previously published cases to 17. It was described as a subtle rearrangement frequently not visible by conventional cytogenetic analysis but manifesting itself as a monosomy 20 (−20) with or without an apparent deletion of the short arm of chromosome 9 [del(9p)]. Fluorescence in situ hybridization (FISH) confirmed dic(9;20) in the majority of cases. In five cases the dicentric nature of the derived chromosome was confirmed by C-banding alone.2 Cosmid and yeast artificial chromosome (YAC) probes demonstrated the loss of most of the long arm of chromosome 20.1,2 These reports showed an association of the abnormality with CD10+ precursor B-lineage ALL. The Leukaemia Research Fund/United Kingdom Cancer Cytogenetics Group Karyotype Database in ALL (LRF/UKCCG Karyotype Database) identified monosomy 20 in 8/399 adults and 51/2391 infants and children with successfully G-banded karyotypes. This report describes the results of FISH analysis using whole chromosome ‘paints’ (wcp) and centromeric Correspondence: C Harrison, Department of Haematology, The Royal Free and University College Medical School, Pond Street, London NW3 2QG, UK; Fax: 44 171 794 1417 Received 8 July 1999; accepted 23 September 1999
Diagnostic bone marrow samples from patients with ALL entered to the MRC treatment trials were processed for cytogenetic studies in the participating UKCCG laboratories. Gbanded slides were prepared and analyzed in these laboratories, then submitted to the LRF/UKCCG Karyotype Database for review. Karyotypes, described according to the International System for Human Cytogenetic Nomenclature (ISCN),4 were entered into the LRF/UKCCG Karyotype Database computer.
FISH studies The UKCCG laboratories provided fixed cell suspensions of cytogenetic preparations from 25/59 patients with −20 for further FISH studies. Dual-color FISH was performed using wcp 9, directly labeled with FITC, and wcp 20, labeled with Cy3 (Cambio, Cambridge, UK), and, in a separate hybridization, the two centromeric probes, biotinylated chromosome 9 beta satellite probe, D9Z5, and digoxigenin labeled chromosome 20 alpha satellite probe, D20Z1 (Oncor, Gaithersburg, MD, USA). Other wcps or specific probes were used to characterize additional chromosomal changes in some of the more complex karyotypes. Probes were used according to the manufacturers’ instructions. Centromeric probes were detected using avidin–FITC and rhodamine-conjugated antibodies. The DAPI counterstain facilitated identification of the hybridized chromosomes. Cells were analyzed using a Zeiss Axioscop fluorescence microscope (Welwyn Garden City,
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UK) with specific filters. Image analysis was carried out using Smart Capture software (Vysis, Richmond, UK). Some of the more recent patients were investigated for the presence of t(12;21)(p13;q22) by FISH using probes for ETV6 and AML1 (Vysis, UK), or reverse transcriptase polymerase chain reaction (RT-PCR) for evidence of the ETV6/AML1 fusion gene associated with this translocation.
Results
Cytogenetic studies The G-banded cytogenetic results for the 25 patients are summarized in Table 1. Monosomy 20 occurred as the sole chromosomal abnormality in the stem line in five patients (1–5), with an additional abnormality of 9p in a further 15 patients (9–21, 23 and 24) (Figure 1). Two patients (18 and 19) were originally suspected of having a dic(9;20) from cytogenetic studies. One of these (19) was originally described as having two copies of chromosome 20 together with a dic(9;20). Reinvestigation of the slides revealed a small population of cells with one copy of chromosome 20 and the dicentric chromosome. Other karyotypic changes were random except for trisomy 21, which was found as an accompanying cytogenetic change in eight patients (6–8, 13, 15, 16, 18 and 20).
FISH studies The results of FISH investigations, in the form of partial karyotypes, are given in Table 1. The presence of the dic(9;20) was demonstrated in 20 patients by dual-color FISH, initially with wcps (Figure 2) confirmed by centromeric probes (Figure 3) for chromosomes 9 and 20. For patient 17 wcps confirmed the translocation between 9 and 20 although centromeric probes only showed a weak signal for chromosome 20. A much stronger signal for 20 centromere was seen on the der(20)t(20;6;11) which from G-banded studies had been previously described as a marker. For patient 19 FISH disclosed a complex pattern of clonal evolution, a small stemline with dic(9;20) alone and a major side-line with an additional copy of chromosome 20 which had evolved into two further side-lines with second copies of chromosomes 9 and dic(9;20), respectively. In five patients with −20 (21–25), three of whom had associated abnormalities of 9p (patients 21, 23 and 24), FISH showed no evidence of dic(9;20). Patient 25 was the only case of a true monosomy 20 and in the other cases cryptic rearrangements of chromosome 20 were identified. Complex rearrangements involving chromosomes 9, 18 and 20 were disclosed in patient 21. The marker chromosomes in patient 22 were redefined as del(20q) and add(20q) and in patient 23 an add(20q) was revealed. For patient 24 a true deletion of 9p was confirmed and the add(8q) was identified as a der(20)t(8;20)(q1;p1). This patient was also shown to have a t(12;21)(p13;q22) by wcps 12 and 21 and ETV6 and AML1 probes (Vysis, UK). There was no evidence of ETV6/AML1 fusion in seven of the cases with a dic(9;20) and in two out of three of the cases without a dic(9;20) for which cells were available for testing, as indicated in Table 1. Leukemia
Clinical and follow-up data Clinical and follow-up data for the dic(9;20) positive patients are given in Table 1. The majority of patients were classified as CD10+ pre-B or common ALL and one was classified as TALL (CD2+, CD7+, CD10−) (patient 17). The finding of a chromosomal abnormality involving the chromosome band 14q11, t(8;14)(q24;q11), in a proportion of cells, supported this T cell immunophenotype. Follow-up time ranged from 1 to 80 months (median 37 months) but was less than 18 months for seven patients including the T cell case. Four patients relapsed at 2, 22, 28 and 47 months and two of these later died.
Discussion Twenty new patients have been identified with dic(9;20) bringing the total number of reported cases to 37. Clinical and cytogenetic details of the previously published cases are given in Table 2. The dic(9;20) was the sole abnormality in the stemline in 19/37 cases indicating that it is a primary chromosomal change. However, in our study one case with a T cell immunophenotype was found with an associated abnormality of 14q11, t(8;14)(q24;q11). An interesting feature of this case was the finding of the t(8;14)(q24;q11) in only a proportion of cells with the dic(9;20). Although this translocation is known to be a characteristic primary change in T-ALL, in this case it appears to be secondary to all other chromosomal abnormalities, including dic(9;20). This raises the possibility that it could have been lost from the principle clone. Further, in a previously reported case in the series of Rieder et al1 dic(9;20) was found in association with the Philadelphia chromosome in all cells. These findings suggest that although dic(9;20) is likely to be a primary change it may arise concurrently with other primary changes as has been described for t(9;22)(q34;q11) and t(1;19)(q23;p13).5 The karyotypes were most frequently simple, although three out of the four cases in the series by Heerema et al3 were complex. A range of random chromosomal abnormalities have been reported with dic(9;20). However, 11 cases showed additional copies of chromosome 21, suggesting that this could be a nonrandom change. In five cases in our series there was no evidence of dic(9;20) by FISH. Three had an abnormality of 9p in addition to monosomy 20 and thus appeared as likely candidates for a dic(9;20). In four of these cases chromosome 20 was present as a der(20), partially deleted or involved in different unbalanced rearrangements. Some of these may represent variant dic(9;20) rearrangements which need other probes to identify them. The importance of variant cases will be clarified when more is known about the mechanisms of the dic(9;20) translocation. The finding of a single case with two normal chromosomes 20 in association with dic(9;20) as part of a complex pattern of karyotypic evolution in the majority of cells highlighted another problem in terms of accurate detection of dic(9;20). If it had not been for the suspected dic(9;20) on G-banded analysis this case could have been overlooked. In the case of T-ALL, the dicentric with a very weak centromeric signal for chromosome 20 suggests, either that the break may have occurred within the centromere rather than just below it, or that this may be a constitutional polymorphism. Whether this phenomenon was related in any way to
9/M
14/M
24
25
27
15
4 4
13
c-ALL/pre-B
c-ALL/pre-B
c-ALL pre-B
c-ALL
c-ALL
c-ALL NA
b
BMT at 9 months, second relapse at 10 months. t(12;21) negative by FISH. c t(12;21) negative by RT-PCR. NA, follow-up not available.
a
52/M 49/M
22 23
non dic(9;20) cases 21 2/M
4/F
20
20
13.1 2.4
32/F 11/F
18 19
c-ALL c-ALL/pre-B c-ALL NA pre-B pre-B c-ALL c-ALL/pre-B c-ALL pre-B pre-B c-ALL c-ALL/pre-B c-ALL c-ALL c-ALL/preB T
WBC × 109/l Immunophenotype
134 4 145 32 21 38 10.7 25 6 28 6 80 11.2 536 23 56 450
Age (years)/ Sex
1
7
0.75 NA
19
1+
5+ 6+
51+ 22 47 5+ 46+ 80+ 15+ 26+ 28+ 28 33+ 70+ 5+ 43+ 60+ 49+ 2
1+
7+
1 NA
35+
1+
5+ 6+
51+ 41+ 49 5+ 46+ 80+ 15+ 26+ 28+ 63 33+ 70+ 5+ 43+ 60+ 49+ 17+
Event-free Survival survival (months) (months)
46,XY,+Y,−20
48,XY,−7,+8,−20,+mar1×2,+mar2/47,idem,−21 58–65,XY,+X,+1,+1,+2,+4,+4,+5,+6,+6,+8,t(9;12)(p13;q15), +10,+10,+11,+11,+12,+14,+18,+18,+19,−20,+21,+21[cp] 46,XY,+8,add(8q),del(9)(p21),del(11)(q14q23),−20
45,XY,del(9)(p21),−20/46,idem,+del(20)(q13)/45,idem,del(9)(p12)
45,XX,−20 45,XX,−20 45,XX,−20 45,XY,−20 45,XY,−20/46,idem,+X 46,XX,−20,+21 46,XY,−20,+21 46,XX,−20,+21/48,idem,+2mar 45,XX,del(9)(p21),−20 45,XY,del(9)(p21),−20 45,XY,del(9)(p21),−20/46,idem,+mar 45,XX,inv(7)(p11q22),del(9)(p21),−20 46,XX,add(8)(p11),del(9)(p21),−20,+21 45,XX,del(9)(p22p24),del(11)(q14q23),−20 47,X,−Y,del(9)(p22),−20,+21,+r,+r/48,idem,+21 49,XX,+X,del(9)(p22),+10,−20,+21,+21/49,idem,del(17)(p13) 46,XX,del(6)(q1?),add(7)(q34),del(9)(p21),ins(13;?)(q;?),−20,+mar/ 47,idem,+19/47,idem,t(8;14)(q24;q11),+19 46,XX,dic(9;20)(p11~13;q11),+21 45,XX,dic(9;20)(p11-13;q11)/46,idem,+20 /52,idem,+6,+8,+9,+12,+18,+22 46,XX,dic(9;20)(p11~13;q11),t(9;14)(p21;q11),+21
G-banded karyotype
Clinical, cytogenetic and FISH details of patients with −20 detected by conventional cytogenetic methods
dic(9;20) cases 1 1/F 2 2/F 3 2/F 4 2/M 5 5/M 6 2/F 7 5/M 8 2/F 9 5/F 10 2/M 11 17/M 12 2/F 13 14/F 14 6/F 15 4/M 16 2/F 17a 4/F
Patient No.
Table 1
del(9p),del(11q),t(12;21)(p13;q22), der(20)t(8;20)(q1;p1) −20
dic(9;18),del(20)t(18;20)/idem, del(9p)/idem,+18,−der(20)c add(20?q)×2,del(20?q) der(9)t(9;12),del(12q),+18,add(20q)
dic(9;20) dic(9;20)/idem,+20/idem, +9,+20/idem,+dic(9;20),+20b dic(9;20),t(9;14)b
dic(9;20) dic(9;20) dic(9;20) dic(9;20)b dic(9;20)/idem,+X dic(9;20) dic(9;20)b dic(9;20),+21/idem,+2marc dic(9;20)c dic(9;20) dic(9;20) dic(9;20) dic(9;20) dic(9;20) dic(9;20) dic(9;20), +10,+21,+21 t(8;14),dic(9;20),der(20)t(20;6;11)b
Partial karyotype by FISH
dic(9;20) in ALL R Clark et al
243
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dic(9;20) in ALL R Clark et al
244
Figure 1
G-banded Karyotype from case 9 showing del(9p) and monosomy 20 (arrowed).
Figure 2 Dual-color FISH using wcps for chromosome 9 (green) and chromosome 20 (red). A normal chromosome 9 and 20 can be seen in addition to the dic(9;20) (arrowed).
the der(20) with a strong centromeric signal found in the same cells, requires further investigation. Dic(9;20) has been previously described as a chromosomal change associated with precursor B lineage ALL.1–3 This study presents the first report of its association with a T cell immunophenotype. Follow-up of 30 children with this abnormality has now been reported, of whom 17 have been followed for between 24 and 124 months. Eight patients have relapsed between 2 and 48 months (median 23.5 months) but only two have died, one of them in second relapse 34 months later. For the remaining six patients durable second remissions of Leukemia
Figure 3 Dual-color FISH with probes to the centromeric regions of chromosome 9 (green) and chromosome 20 (red). Juxtaposition of the two signals indicates the dic(9;20). The normal chromosome 9 and 20 are also shown.
between 15 and 101 months (median 35.5 months) have been reported. A larger series and longer follow-up of patients with dic(9;20) is needed but it appears that the overall survival of patients with this translocation may be good. Whether prognosis is linked either to the 9p deletion or the dicentric chromosome is unknown. The interferon (INF) ␣ and  gene clusters, CDKN2/p16INK4A/MTS1 and CDKN2B/p15INK4B/MTS2 genes localized to 9p, are frequently deleted in ALL.6–10 Results are conflicting in relation to outcome in patients with these deletions.9,11–13 Other dicentric chromosomes have
4/F 4/F
2/M 4/F 5/F 2/F 4/M 13/F 7/F 57/F
2/M 4/F
12/F
7/M
12 22
32 42 52 62 72 82 92 102
13 23
33
3
5
57
210 22
23 16 54 117 5 18 42 34
145 31
4 40 138
WBC × 109/l
c-ALL/pre-B
c-ALL/pre-B
c-ALL/pre-B c-ALL/pre-B
c-ALL c-ALL pre-B pre-B pre-B pre-B c-ALL c-ALL
c-ALL c-ALL
c-ALL/pre-B c-ALL c-ALL
Immunophenotype
a Karyotype in relapse. Superscripts 1, 2 and 3 refer to the Ref. number. NA, follow-up not available.
4
45/M 64/F 32/M
Age (years)/Sex
NA
23
30+ 36+
5+ 48 23 61+ 39+ 123+ 24 1
23 23+
NA NA NA
NA
38
30+ 36+
6+ 94+ 124+ 62+ 40+ 124+ 61+ 2.5
57+ 24+
45+ 10+ 8
Duration of 1st CR Survival (months) (months)
Clinical and cytogenetic details of cases with a dic(9;20) in the literature
11 21 31
Patient No.
Table 2
45,XY,dic(9;20)(p1;q11)/44,idem,−22 48,XX,+8,dic(9;20)(p11;q11),+10,+21,+dmin/49,idem,+X/49,idem,+18 /47,idem,del(4)(p14),−17,der(18)t(17;18)(q11,2;q23) 50,XX,−2,+del(2)(p21)×2,del(5)(q22q33),del(9)(p22),dic(9;20)(p11;q11), +16,+22,+del(22)(q11),+mar 46,XY,add(1)(q32),−5,add(7)(p22),dic(9;20)(p11;q11),add(12)(p13),+mar1,+mar2
45,XX,dic(9;20)(p1?3;q11) 46,XX,dic(9;20)(p1?3;q11),+21/46,idem,add(14)(p11) /47,idem,+dic(9;20) (p1?3;q11) 45,XY,dic(9;20)(p1?3;q11) 45,XX,dic(9;20)p1?3;q11),del(13)q1q3)/45,idem,del(9)(q22q32苲33)a 45,XX,dic(9;20)(p1?3;q11),del(13)(q14q34) 45,XX,dic(9;20)(p1?3;q11) 46,XY,dic(9;20)(p1?3;q11),+21 45,XX,dic(9;20)(p1?3;q11)/46,idem,+dic(9;20)(p1?3;q11) 45,XX,dic(9;20)(p1?3;q11) 45,XX,dic(9;20)(p1?3;q11)
45,XY,del(9)(p13p22),−20 45,XX,del(9)(p13p22),−20 45,XY,der(9)t(9;22)(q34;q11)dic(9;20)(p11;q11.?1),−20,der(22)t(9;22)(q34;q11)
G-banded karyotype confirmed by FISH and/or C-banding
dic(9;20) in ALL R Clark et al
245
Leukemia
dic(9;20) in ALL R Clark et al
246
been described as established chromosomal changes in ALL.14–18 The dic(9;12)(p11苲13;p11苲12), like the dic(9;20), results in deletion of 9p and identifies an important subgroup of CD10+ B-lineage ALL which has a good prognosis.15,16 The outcome has been reported to be relatively good for patients with monosomy 20 as the sole chromosomal abnormality, raising the possibility that they may be cases of unrecognized dic(9;20).19 This report has confirmed dic(9;20) as a recurring chromosomal abnormality in ALL. It has been shown to masquerade as a monosomy 20 with or without a cytogenetically visible deletion of 9p. We have shown that not all patients with −20 and del(9p) have a dic(9;20). Hence, FISH is essential for the accurate detection of this abnormality. It is still unknown whether the 9p and 20q breakpoints are identical in all cases. The significance of dicentric chromosomes depends on whether they contribute to overall chromosomal gain or loss, or if the translocation results in the formation of a fusion gene. The stability, non-random involvement and consequences of dicentric chromosomes as clonal abnormalities in the hematological malignancies have been discussed by Berger and Busson-Le Coniat.18 There is now a need to investigate the breakpoints on chromosomes 9 and 20 by FISH and molecular studies. This would allow variant or masked rearrangements to be identified and would help in the understanding of the pathogenesis of dic(9;20) in patients with ALL. Acknowledgements The authors wish to thank the members of the following UKCCG laboratories for providing patient samples: Bristol; Cambridge; Glasgow; Leeds; Liverpool; Manchester; Newcastle; Oxford; Salisbury; Sheffield; University College Hospital, London: the Medical Research Council Leukaemia Working Parties, in particular the co-ordinators of the MRC Infant protocol (J Chessells), UKALL XI (I Hann and F Hill), ALL 97 (J Lilleyman, S Kinsey and C Mitchell), UKALL XII (I Franklin): R Clack and J Burrett, Clinical Trial Service Unit, Oxford: the Leukaemia Research Fund for financial support: and Professor Mel Greaves for providing the RT-PCR results to exclude ETV6/AML1 fusion in some cases. References 1 Rieder H, Schnittger S, Bodenstein H, Schwonzen M, Wormann B, Ludwig WD, Hoelzer D, Fonatsch C. dic(9;20): a new recurrent chromosome abnormality in adult acute lymphoblastic leukemia. Genes Chromosom Cancer 1995; 13: 54–61. 2 Slater R, Smit E, Kroes W, Jotterand Bellomo M, Muhlematter D, Harbott J, Behrendt H, Hahlen K, Veerman AJP, Hagemeijer A. A non-random chromosome abnormality found in precusor-B lineage acute lymphoblastic leukaemia: dic(9;20)(p1?3;q11). Leukemia 1995; 9: 1613–1619. 3 Heerema NA, Maben KD, Bernstein J, Breitfeld PP, Neiman RS, Vance GH. Dicentric (9;20)(p11;q11) indentified by fluorescence in situ hybridization in four pediatric acute lymphoblastic leukemia patients. Cancer Genet Cytogenet 1996; 92: 111–115.
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