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M Bernard1, F Lemée2, F Picard2, C Ghandour3, B Drenou4, PY Le Prise1 & T Lamy1
1Service d'Hématologie Clinique, CHU de Rennes, France
2Laboratoire de Génétique et Biologie Cellulaire, CHU de Rennes, France
3Unité d'Hématologie, Clinique de Cesson-Sevigné, France
4Laboratoire d'Hématologie, CHU de Rennes, France
Correspondence to: T Lamy, Service d'Hématologie Clinique, Hôpital Pontchaillou, CHU de Rennes 35033, France; Fax: 33 2 99 28 41 61
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| Introduction Jumping translocation (JT) is defined as a translocation of the same fragment of donor chromosome on to the ends of various recipient chromosomes. Recipient chromosomes are usually random, and vary from one patient to another. These cytogenetic abnormalities may be constitutional or acquired. A few cases, mainly involving the long arm of chromosome 1, have been reported in hematological malignancies. Fewer than 25 cases have been described, particularly in multiple myeloma, high-grade non-Hodgkin's lymphoma and acute leukemia. Despite the rarity of this event, it seems that JT is associated with poor prognosis. Here we report a case of JT involving the 3q13 segment in a patient with AML5 following chronic myelomonocytic leukemia. Materials and methodsCase report A 59-year-old patient was diagnosed with chronic myelomonocytic leukemia (CMML) in 1992. Because of indolent disease and moderate thrombocytopenia he was not treated for 5 years until he developed cutaneous leukemic involvement, fever, diffuse bone pain, hepatosplenomegaly, and cerebral spinal fluid infiltration with blast cells. Blood examination showed: WBC 65  109/l with 21% of monocytes and 58% of blast cells, hemoglobin 8 g/dl, platelets 20 109/l. Coagulation tests showed disseminated intravascular coagulation. Bone marrow aspirate revealed 72% of blast cells and AML5b FAB subtype was diagnosed. Immunophenotyping performed on bone marrow cells revealed the expression of CD34, CD33, CD13 and CD11b. The patient underwent an anthracycline-based chemotherapy regimen leading to a transient partial remission. He died of progressive disease 6 months later. Cytogenetic and fluorescence in situ hybridization (FISH) findings Cytogenetic analyses were performed on bone marrow cells using 24-h culture in RPMI-1640 medium with 20% FCS. Seventy-two and 25 metaphases were analyzed in R-banding on diagnosis of AML5 (December 1997) and clinical remission (June 1998), respectively. The same samples were also analyzed by FISH techniques using whole chromosome painting (WCP) of chromosome 13 and 3 (Oncor, Gaithersburg, MD, USA), and all human telomeric sequence probes (Oncor). ResultsConventional cytogenetic analysis Karyotyping on diagnosis of AML5 demonstrated multiple clones as illustrated in Table 1. In 50 out of 72 metaphases, JT was observed leading to a partial trisomy of the long arm of chromosome 3. The jumping segment of the donor was always translocated on to a telomeric region. The telomeric segments of these recipient chromosomes were as follows: 14p (23 mitoses), Xp (11 mitoses), 15p (5 mitoses), 1p (4 mitoses), 10p (4 mitoses), 18q (3 mitoses), and also Yq, 3p, 14q (1 mitosis) (Figure 1a and b). The breakpoint on chromosome 3 seemed to be located at q13.3 rather than q21. Each clone with JT had aneuploidy with trisomy 8 or tetrasomy 8. In addition, there were also abnormal clones without JT but with aneuploidy, tetrasomy 8 or pentasomy 8. Seven metaphases showed 46, XY karyotype. Six months later, on clinical remission, four out of 24 metaphases displayed the same JT but only on to 11p which was not involved in the first karyotype. The remaining 20 metaphases showed 46, XY karyotype. Molecular cytogenetic analysis (FISH) According to the morphology of the jumping segment which displayed either 13q or 3q features, we performed whole chromosome painting of 13 and 3. This enabled us to assess partial trisomy 3 (Figure 2). Telomere probes showed deletion of the telomeric region of the following recipients: der Y as shown in Figure 3, derX, der10, and der14p11. Each 47 chromosome metaphase was supposed to contain a jumping segment (Table 1). In these metaphases, we never observed an interstitial signal of telomeric sequences (data not shown). DiscussionJumping translocation is a very rare event, firstly described in 1979 by Lejeune et al,1 and so far 39 JT cases have been reported in the literature. In the cases of constitutional JT (nine cases reported), chromosome 15 is usually involved.2,3 Most of the acquired JT (30 cases) have been described in solid tumors (ie carcinomas, renal tumors),4,5 and in hematological malignancies. Jumping translocations may occur in multiple myeloma,6 non-Hodgkin's lymphoma,7 and acute de novo or secondary leukemia.7,8 To our knowledge, only 13 cases of AML associated with JT have been described: one case of AML0,7 one case of AML2,8 two cases of APL,9,10 seven cases of AML4/5,8,11,12,13,14,15,16 and one case of AML7.17 One other unclassified AML case following juvenile chronic myelomonocytic leukemia has been reported.18 We report on another JT in a case of AML5 after a 5-year untreated chronic myelomonocytic leukemia. In this case, we did not perform karyotyping at diagnosis of myelodysplasia and we cannot assume that JT was acquired at the time of AML transformation. However, JT generally occurs in the course of leukemia following myelodysplasia, sometimes associated with trisomy 8 (Table 2). Indeed, jumping translocation is probably a secondary acquired chromosomal abnormality, the primary event probably being trisomy 8. In the course of AML5, karyotypic abnormalities are infrequent and usually involve 11q 23 especially with t(9:11) or t(11:19). Our case, the eighth case of AML4/5 with JT, is the second one involving 3q13 as a segment donor leading to a partial trisomy 3q. Interestingly, in three other cases of AML the breakpoint of the segment donor is located in a very close region (3q21) also associated with partial trisomy 3q. One of the consequences of JT involving the 3q segment could be the amplification of genes such as CDC25, BCL6, and MDS1 (myelodysplasia syndrome 1), located in the same region and known to be involved in oncogenesis.19 In the cases of acquired JT, the donor chromosome is generally the long arm of chromosome 1. The JT breakpoint is sometimes located in regions known to contain DNA repetitive sequences, such as centromeres or the pericentromeric heterochromatin region. Nevertheless, the breakpoint may be observed in other regions as illustrated by the recent report of Hatakeyama et al20 which identified a novel human gene JTB at 1q21 encoding a transmembrane protein. Three other donor chromosomes have been reported: 7q in a case of lymphoid blast crisis of CML, 3q and 11q in other cases of AML.8,10,11,18 The recipient region is most often telomeric or subtelomeric containing repetitive sequences which are known to enable recombination. During cell proliferation, the telomeric length decreases on each cell division leading to chromosome instability unless telomerase activity is reactivated.21 It would be interesting to assess such activity in the JT cases. In two recent reports of JT, it has been shown that the telomeric sequences were maintained.12,20 In our case, no telomeric hybridization was found on the recipients. It has been suggested that transformation of myelodysplastic syndrome is associated with excessive telomere shortening which in itself favors recombinations.21 This could explain the loss of telomeric repeat sequences observed in our case. It is noted that the majority of AML associated with JT derived from a monocytic lineage: as shown in Table 2, eight out of 14 (57%) cases are AML4/5 FAB subtypes. Although most of the cases of JT previously reported are associated with a poor clinical outcome, prognostic impact of JT is difficult to assess given the few cases described. However, all but two patients described in the literature died of progressive disease. Whether JT is a causal event of leukemic transformation or a secondary event remains to be determined. Chemotherapy may influence cytogenetic results: in this case, clinical response may be associated with clonal selection of a recipient chromosome and loss of initial abnormalities. Transient complete karyotype normalization has also been described.9 Although JT is a rare event when studied by standard metaphase analysis, segmental JT may be more frequent using FISH. In a recent paper, Tanaka et al found segmental JT of 9q34 associated with abl amplification gene in three of nine secondary AML.23,24 A case of MLL segmental JT has been also described in a case of secondary AML.25 Segmental JT is potentially a new form of gene amplification. The frequency of JT remains very low but could be underestimated. We suggest that JT occurs preferably in cases of AML-transformed myelodysplasia, with myelomonocytic lineage, and associated with trisomy 8. We report the second case of JT occurring in the 3q13 segment and the fifth involving 3q: this might be a non-random abnormality. It would be interesting to determine whether there is a crucial gene involved in oncogenesis of AML4/5 at this site.
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