Document adDzLROrJ2oYX4XY3Dp3Xjzy

1990: 75~473-6. INV(12) (p13qll) AND DICENTRIC CHROMOSOMES IN A SECONDARY LEUKAEMIA WITH BASOPHILIA * JEAN-LOUP HURET,AND& BRIZARD,FRANCOIGSUILHOTD, OMINIQUE COUET, MICHELE SCHOENWALD, JOHN RK SAVAGE, JOSEPH TANZER we report on a case of secondary myelodysplasia with m p h i a . A karyotwe showed 1) the involvement of 12p, .&h should be related to the basophilia and/or to previ- drug exposure, and 2) the unexpected presence of three dfierent dicentric chromosomes. $& WORDS: Chronic myelomonocytic leukaemia, secondary jmkaemia, basophilia, dicentric chromosomes. Chromosome 12p rearrangements in myeloid malignanies have been reported in chronic myelomonocytic leukae=;ia I, in acute non lymphocytic leukaemia (ANLL) type :with basophilia:', and in other myelodysplastic syn- zomes and ANLL, mostly secondary to carcinogen ex-we4. We report a case of secondary chronic my&monocytic leukaemia (CMML) in transformation with wphilia and a 12p rearrangement. This case also exhibitA numerous extra copy segments 8q, especially 8q23 + ~ e r ,and three various dicentric chromosomes. - L-GE REPORT A 69-year-old woman was referred to us in February 1% with hyperthermia and asthenia. She had previously XI a malignant melanoma in 1976 treated by surgery and *chemotherapy (vinblastine, thiotepa, methotrexate, =domonomicine and dacarbazine), which was interrupted 199. At presentation in 1986, there was no splenomegaly ZGX enlarged lymphnodes. Haemoglobin was 9.4 g/d, WBC --as 27 x 109/1 with 61070 neutrophils, 14% basophils, 8% .mhocytes, 14% monocytes, 20io immature cells and 1% *. Platelet count was 52 x IP/l. Bone marrow smears wrc hypercellular with 20% blasts, 9% basophils and a e d myelodysplastic features affecting all cell lines; a W L in transformation, according to the FAB classifi- `This case was cited in (15). FrOm the Dkpartement d'Hkmatoiogie et Oncologie Mkdicale, URA 1338, H6pital Jean Bernard, Poitiers, France, and Radiology Unit, Chilton, Didcot, Oxon, UK. aauthors wish to thank Martine Potiron, Micheline Martin OrlMwie-Andree Landreau for technical assistance. This work 7svppOrted by Association pour la Recherche sur le Cancer and -k Nationale contre le Cancer. &bed February 14, 1990; accepted May 16, 1990. h p o n d e n c e : Dr. J.L. Huret, Cytogknktique Lab. .y6.oorogie, CHU La Mil&rie, F46021 Poitiers, France. cation was diagnosed. The bone marrow karyotype (direct analysis, RHG and C bandings, 50 mitoses analysed) was 46, XX [4 mitoses]/45, XX, de1(5)(q14q34), -8, +dic(l)(pll), -6, -12, +dic(6; inv(l2)) (p22; (p13qll)) [15 mitoses]/46, XX, del(5q), -8, +dic(8), +dic(8), -6, -12, +dic(6; inv(l2)) [29 mitoses]/46, XX, del(5q), -8, +dic(8), -6, -12, +dic(6; inv(l2)), +8p+ [2 mitoses]. In the detailed system for chromosome aberrations dic (6; inv(l2)) was 6qter -+ 6p22::12qll -+ 12p13::12qll + 12qter, and 8p+ was 8qter -+ 8q23::8p22 + 8qter. No improvement was noted with chemotherapy. A frank acute non lymphoblas- tic transformation occurred five months after diagnosis (WBC was 2 2 x 109/1 with 30% blasts and 8% basophils). A karyotype from bone marrow (direct analysis, 24-hour and 48-hour culture, RHG and C bandings, 31 mitoses ana- lysed) was 46, XX [l mitosis]/46, XX, del(5q), dic(6; inv(l2)), +dic(8), 8p+ [13 mitoses]/46, XX, del(5q), dic(6; inv(l2)), +dic(8), 8p+, dic (3; 8) (q24; p l l ) [ l l mi- toses]/47, XX, del(5q). dic (6; inv(l2)), +dic(8), 8p+, + DM [4 mitoses]/46, X del(X)(q2?5), del(5q), dic(6; inv(l2)), +dic(8), 8p+ [2 mitoses] [Fig. 11. In the detailed system dic(3;8)(q24;pll) was 3pter -+ 3q24::8pll 8qter. The pa- -+ tient died in February, 1987 from sepsis and haemorrhagcs secondary to bone marrow insufficiency. DISCUSSION A pericentric inversion of chromosome 12 is a rare anomaly. Only 6 previous cases with well-defined breakpoints have been published, 5 of which occurred in myeloid malignancies '-lo. The breakpoint in the short arm has been located in p12-p13, whilst the breakpoint in the long arm has been found dispersed in q l l , q13, q14, q21 and q23. An inv peri(l2)) has been found associated with de1(5q)(3 times), del(6p)(twice), del(l3q) or monosomy 13 (twice), and these associations are unlikely to be random. Basophilia of high degree is quite unusual in haematological malignancies except in chronic myelogenous leukaemia. However, such a basophilia has been described in cases of M2 acute leukaemia with 12p rearrangements '. More rarely, 12p rearrangements are associated with hypereosinophily l1 I2, and the existence of a common basophil-eosinophil progenitor has been ascertained 13. It is thus possible that a malignant event lying on rearranged chromosome 12p involve a stem cell retaining the potentiality to differenciate along multilineage pathways. Alternatively, chromo- 474 J.L. Huret et al. "1 breakpoints, such as in the present report, a drug could be the cause, and the basophilia a conseq 12p rearrangement. were found in each abnormal subclone in the p Furthermore, these extra copies were provided e119 H.4 Fig. 1. - Partial karyotypes with RHG banding (above) showing - -structural anomalies: dic(6;12): 6qter -+ 6p22::12qll -, 12p13::12qll -+ 12qter 8p': lqter 8q23::8p22 lqter dic(l)(pll): lqter -+ 8pll::8pll + lqter -del(5q) and below: dic(3;l): fpter 5q24::lpll -, lqter. Below: partial karyotypes with both RHG and C bandings on the same mitoses showing the dicentric chromosomes. Large arrows; detectable centromeres; small arrows: presumed centromeres. The centromere of 12 has moved close to 6p22, confirming the inversion. To be noted that C banding is not present at the centromere of the rearranged chromosome 6. some 12p rearrangements have also been described in leukaemia following drug exposure for various cancers 4. It is therefore probable that the presence of a basophilia and the appearance of a secondw leukaemia refer to two usually unrelated events on chromosome 12 short arm. In the present report, 12p rearrangement was found in a secon- sets in the first sample, progressing to 5 to 6 s second sample. MYC is mapped in 8q24, an amplification has been shown to be correlated progression in various malignancies. However, aunknown if these extra gene copies were expressed and mnGtherefore played a role in the progression of this myelodysplastic syndrome. J*& It is striking in this case that each chromosomal anoJm, ly (del@@, 6p involvement, 12p involvement, ...) see&'& add a touch of specificity to the general haematologicai ture (Table 1). This can be compared to the appeara& of a t(15;17) or of a dic(9;12), respectively, in a p r o m s locytic and a B lymphoblastic transformation of a chronic myelogenous leukaemia with t(9;22) 'I. Table 1. - Karyotypic anomalies in relarion to the presenrc of various specifciries in rhis leukaemia. I 1 Anomaly Related specificity Referme del(5q) dsecondary myelodyplasia ,(14) 6p involvement + secondary anomaly (evolution of (15) ' \ t h e disease and/or L secondary leukaemia I (16) copies leukaemia with basophilia >econdary leukaemia 1 8q23-2 extra-?+ progression of the disease i t(2) (41 i I I I An unexpected feature was that three different dim- tric chromosomes were found in the present case: dic(6;inv(l2)), dic(8), and dic(3;8). This could be related to previous chemotherapy treatment. A mitosis with banding (Fig. 2) was shown to exhibit a rearranged dseP- tric chromosome (i.e. with change in chromosome lenBtb and centromeric indexes). Unfortunately, this mitosis was not R or G banded previously t o C-banding, and the ' I I I / Dicentric chromosomes in CMML 475 to di 12p (potenzialmente importante per la basofilia) e 3 diversi cromosomi dicentrici. Fig. 2. - Rearranged dicentric chromosome with C-banding (right) and a chromosome C (8,lO or 12)fleft). included for comparison of the length of the dic. act m e of the rearrangement is unknown. However, this fmding could be in favour of the existence of a true dicentric suniving through a breakage-fusion-bridge cycle. By another way (i.e. a double bridge at anaphase), true dicentric chromosomes have already been ascertained to occur in malignancy 19. It is impossible to say if all the centromeres of the dicentric chromosomes were active in our case. In the case of true dicentric chromosomes, especially those With a large intercentromeric region such as dic(3;8), the cells bearing these chromosomes should be highly unstable a d selected against, but the cell lines appeared to be well established. The main hypothesis would be that these particular dicentrics gave specific selective advantages to the cells Carrying them to counterbalance a gross mechanic disadvantage. These specific advantages could be those involved in the malignant process and discussed above. The alternative hypothesis could be that an unknown disregulation favoured the repeated <<fallfree,, of dicentric chromOSOmes to maintain their presence in the abnormal clones. Iw(l2)(p13qll) E CROMOSOMI DICENTRIC1 IN uh' CAS0 DI LEUCEMIA SECONDARIA CON BASOFILIA -- descritto un cas0 di leucemia secondaria con ba- wfhL'e.same citogenetico ha dimostrato il coinvolgimen- Note added after submission: A very comprehensive study contrue and pseudo dicentrics has recently been published (Vig a a* b c e r Genet Cytogenet 1989; 43: 151). REFERENCES 1. Tanzer J, Lessard M, Guilhoi F, Brizard A. Remaniement du petit bras du chromosome 12 dans les leucemies myelomonocytaires chroniques (LVMC). Noui- Rev Fr Hematol 1987; 29: 65-8. 2. Daniel MT, Bernheim A, Flandrin G, Berger R. Leucemie aigue myeloblastique (M2) ava- atteinte de la lignee basophile et anomalies du bras court du chromosome 12 (12p). CR Acad Sci, Paris 1985; 301: 299-301. 3. Second Mic Cooperative Study Group (1988). Morphologic, immunologic and cytogenetic (hlIC) working classification of the acute myeloid leukemias. Cancer Genet Cytogenet 1988; 30: 1-16. 4. Berger R, Bernheim A, Le Coniat M, et al. Abnormalities of the short arm of chromosome 12 in acute nonlymphocytic leukemia and dysmyelopoietic syndrome. Cancer Genet Cytogenet 1986; 19: 281-9. 5. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodpplastic syndromes. Br J Haematol 1982; 51: 189-99. 6. ISCN (1985): An International Sptem for Human Cytogenetic Nomenclature, Harnden DG and Qinger HP eds. Cytogenet Cell Genet (Karger, Basel 1985). 7. Mitelman F, Manolova Y, hfanolov G, et al. High resolution analysis of the 5q-marker chromosome in refractory anemia. Hereditas 1986; 105: 49-54. 8. Larripa I, Mecucci C, Testoni N, et al. Inversions of chromosome 12 in human malignancies. Cancer Genet Cytogenet 1987; 28: 113-8. 9. Rege-Cambrin G, Mecucci C, Tricot G, et al. .4 chromosomal profile of polycythemia vera. Cancer Genet Cytogenet 1987; 25: 233-45. 10. Huret JL, Brizard A, Briault S, Dreyfus B, Giraud C, Tanzer J. Two additional cases of inv(l2) in human malignancies. Cancer Genet Cytogenet 1988; 32: 309-11. 1 1 . Keene P, Mendelow B, Pinto MR, et al. Abnormalities of chromosome 1 2 ~ 1 3and malignant proliferation of eosinophils: a non random association. Br J Haematol 1987; 67: 25-31. 12. Huret JL, Brizard A, Benz-Lemoine E et al. Translocation t(12;13) (p13.3;q12.2) is not restricted to lymphoid malignancies: Report of a further case with hypereosinophily. Leukemia Lymphoma, submitted. 13. Denburg JA, Telizyn S, Massner H et a]. Heterogeneity Of human peripheral blood eosinophil-type colonies: evidence for a common basophil-eosinophil progenitor. Blood 1985; 66: 312-8. * 14. Van den Berghe H, Vermaelen K, Mecucci D, Barbieri D, Tricot G. The 5q-anomaly. Cancer Genet Cytogenet 1985; 17: 189-255. 15. Huret JL, Schoenwald M, Brizard A, Guilhot F, Vilmer E, Tanzer J. Chromosome 6p rearrangements appear to be secondary changes in various haematologiral malignancies. Leukemia Res 1989; 13: 819-24. 16. Mecucci C, Michaux JL, Louwagie A, Boogaens M, Van den Berghe H. The short arm of chromosome 6 is non randomly rearranged in secondary myelodysplastic syndromes. Cancer Genet Cytogenet 1988; 31: 147-55. 17. Berger R, Bernheim A, Daniel MT, Flandrin G . T(15;17) in a promyelocytic form of chronic myeloid leukemia blastic cnsis. Cancer Genet Cytogenet 1983; 8: 149-52. , 476 J.L. Huret et al. 18. Solary E, Mugneret F, Guy H, Caillot D, Carli PM, TurcCare1 C. Association of a chromosomal 9;12 translocation with B cell precursor lymphoblastic blast crisis of a Ph+ chronic myelogenous leukaemia. Br J Haematol 1989; 72: 106-12. man autosomes and ed. The cytogenetics New York: Ar Liss, ............. ... .. , I .,... ...-... .....s !:: . . ..I'L I'..