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Mutagen Exposures and Chromosome 3 Aberrations in Acute Myelocytic Leukemia R Lindquist1, AM Forsblom1,ÅO¨ St2 and G Gahrton1

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Mutagen Exposures and Chromosome 3 Aberrations in Acute Myelocytic Leukemia R Lindquist1, AM Forsblom1,ÅO¨ St2 and G Gahrton1 Leukemia (2000) 14, 112–118 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu Mutagen exposures and chromosome 3 aberrations in acute myelocytic leukemia R Lindquist1, AM Forsblom1,ÅO¨ st2 and G Gahrton1 1Department of Hematology, Karolinska Institutet at Huddinge University Hospital, Huddinge; and 2Department of Pathology and Cytology, Karolinska Institutet and Medilab, Stockholm, Sweden Thirteen patients with acute myelocytic leukemia (AML) and have had such exposures or other exposures of mutagens such with clonal aberrations involving chromosome 3 were studied. as previous therapies with antineoplastic agents and/or Three patients had monosomy 3, four had trisomy 3, and six had structural aberrations of chromosome 3. In the majority of radiation. cases chromosome 3 aberrations were parts of complex kary- otypes, but in two patients, the abnormalities appeared as sin- gle aberrations, one as an interstitial deletion del(3)(p13p21) Materials and methods and the other as monosomy 3. All breakpoints of chromosome 3 were found in the fragile site regions 3p14.2, 3q21 and 3q26– Patients 27. All patients with monosomy 3 or structural aberrations of chromosome 3 and one of the four patients with trisomy 3 had been exposed to mutagens, such as occupational exposures Thirteen patients with AML and chromosome 3 aberrations to organic solvents and/or petroleum products or treatments were investigated; six males and seven females. The median with irradiation or antineoplastic agents. The association age was 62 years (range 16–84) (Table 1). The patients partici- among mutagen exposure, structural chromosome 3 aber- pated in prospective treatment studies within the Leukemia rations and fragile sites in AML may indicate that targeting of Group of Middle Sweden (LGMS).19,20 Almost all patients with the mutagens to these sites is of importance for the etiology of the disease. Leukemia (2000) 14, 112–118. leukemia in this region are admitted to LGMS hospitals and Keywords: acute myeloid leukemia; chromosomes 3; chromo- enter co-operative treatment protocols. The study was some, fragile site; occupational exposure; megakaryocyte; approved by ethical committee of the Huddinge University mutagen exposure Hospital, Karolinska Institutet. The patients in the range of 16–60 years of age were given courses of drug combinations in randomized studies as fol- Introduction lows: (1) POCAL (prednisolone + vincristine + cytosine arabi- noside + adriamycin + thioguanine) or (2) POCAL-DNA Structural and numerical aberrations of chromosome 3 have (POCAL with adriamycin bound to DNA) or (3) DR been identified in hematological diseases1 as well as in other (daunorubicin) + CYT (cytosine arabinoside).19,20 The elderly human malignancies.2,3 In acute myelocytic leukemia (AML), patients (Ͼ60 years) were treated with (1) DR + CYT or with reports at the Fourth International Workshop on Chromo- (2) CYT or with (3) HIDAC (high-dose cytosine arabinoside) somes in Leukaemia found that 3% of the patients with AML (Table 1). had chromosome 3 aberrations when analyzed with banding techniques.1 Aberrations of chromosome 3 are found in cer- tain regions, 3p14–21, 3q21 and 3q26, in leukemias as well Cytogenetics as in other malignant diseases, suggesting that these aber- rations are non-random events important for the development Bone marrow samples for chromosome analysis were taken of the malignancy.2–4 Previous studies indicated an associ- at diagnosis before cytostatic drug treatments. Bone marrow ation between structural aberrations in the regions 3q21 and cells were analyzed both by direct method21 and by in vitro 3q26 and dysmegakaryocytopoiesis in leukemias of different culture for 24 h without mitogen. Peripheral blood cells were types such as AML,5–7 chronic myelocytic leukemia (CML)8,9 incubated for 48–72 h both with and without phytohemagglu- and myelodysplastic syndrome (MDS).10,11 tinin (PHA) (Burroughs, Wellcome, UK) in RPMI medium with Pedersen-Bjergaard et al12 have shown that chromosome 3 10% calf serum as nutrient medium for bone marrow. For per- aberrations are frequently present in therapy-related, second- ipheral blood the patients own sera were used. For 2 h before ary AML (t-AML) after treatments with irradiation and/or anti- harvesting, the cells were exposed to colchicine to a final con- neoplastic agents. Both balanced translocations involving centration of 0.005 ␮g/ml (Sigma, St Louis, MO, USA) for 3q26 and 11q23 or 21q22, and deletions of chromosome 3 bone marrow and 0.05 ␮g/ml for blood. Hypotonic treatment were observed. Molecular studies have shown that the region with potassium chloride solution 0.075 M was done before 3q21 harbors 10 different breakpoints in leukemia. These are cell fixation with a mixture of 1:3 glacial acetic acid and of combined with reciprocal translocations with other chromo- 100% methyl alcohol. The conventional Q-banding technique somes such as 1, 5, 11, 12 and 15.13 ad modum Caspersson22 was used for chromosome staining Studies of exposures to organic solvents or petroleum pro- and the International System for Human Cytogenetic ducts have indicated an association with the development of Nomenclature (1995) was used for chromosome classi- leukemia.14–18 The aim of the present study was to analyze fication.23 whether AML patients with chromosome 3 aberrations may Morphology Correspondence: R Lindquist, Department of Hematology, Huddinge University Hospital, SE 141 86 Huddinge, Sweden; Fax: (+)46 (8) 58 All bone marrow and blood samples were analyzed by the 58 25 25 same investigator (ÅO¨ ), without knowledge of the results of Received 30 March 1999; accepted 14 September 1999 the chromosome analyses. The diagnostic procedures were Table 1 Blood values, morphological data, survival, time of remission and treatments of 13 patients with AML and chromosome 3 aberrations Patient No. Sex/Age Chrom 3 aberration FAB Hb WBC Platelet Dysmegakaryo- Survival Time of Treatment (g/l) (×109/l) count cytopoiesis (days) remission for AML (×109/l) (days) 60 M/38 +3M272530− 445 324 POCAL-DNA 102 F/77 +3 M5841310 − 100 130 F/62 +3 M2473149 − 726+a 642+ DR+CYT 133 M/16 +3 M2 106 42 86 − 586 260 POCAL- DNA/NOVANTRONE 115 M/62 del(3)(p14–21) M2 67 29 14 − 190 0 DR+CYT 161 M/47 del(3)(p13p21) M2 80 220 36 − 264 90 POCAL/ADR+CYT+VP 72 F/76 t(3;8)(q13–21;p21) M1 74 2 25 − 22 0 CYT+LANVIS t(3;21)(q13–21;q22) R Lindquist Mutagen exposures and chromosome 3 aberrations in AML 179 M/33 del(3)(q21) M4 79 42 16 + 329 96 POCAL/HIDAC+AMSA 143 F/69 del(3)(q21) M5 76 128 338 + 72 0 HIDAC+AMSA/DR- DNA+VP16 et al 148 M/84 t(1;3)(p36;q21) M2 90 5 105 + 52 0 0 (refused) add(3)(q25–29) 68 M/55 −3 M4602426 − 20 0 DR+CYT 158 F/61 −3 M2 109 2 15 − 16 0 HICAC 176 F/76 −3 M2 87 9 117 + 180 0 DR+CYT/POCAL aThe patient died of cancer of the ovary on day 726. Leukemia 113 Mutagen exposures and chromosome 3 aberrations in AML R Lindquist et al 114 based on morphological methods. The French–American– points in the region 3q21 as part of complex karyotypes. One British (FAB) classification of the leukemias was used as pro- patient had a breakpoint at 3q13–21 with two translocations posed by Bennett et al,24,25 with the slight modification of O¨ st of chromosomes 8 and 21, t(3;8)(q13–21;p21), and et al.26 Dysmegakaryocytopoiesis was defined as an abnormal t(3;21)(q13–21;q22) and in addition del(7)(q31). Two patients disturbed thrombocytopoiesis and/or reduction in the number had del(3)(q21) and both of them abnormalities involving of megakaryocytes as well as the presence of cytological chromosomes 5 and 17. One patient had t(1;3)(p36;q21) and abnormal megakaryocytes, especially hypolobulated, small add(3)(q25–29). megakaryocytes in the bone marrow. The CD61 antibody was Five patients had involvements of chromosomes 3 and 17. not used in the analysis. The structural abnormalities were located in the regions 17q10–11 and 17q23–25. One patient had monosomy 17 and one had trisomy 17. Environmental exposure and previous exposures to antineoplastic agents Patient records and interviews with patients or the next of kin Chromosome 3 breakpoints and constitutive fragile were used as sources of information concerning occupational sites and environmental exposures and medication before the diag- nosis of AML. Occupational exposure was defined as full-time daily exposure to organic solvents and/or organic solvent- Constitutive or common fragile sites (c-fra) on chromosome 3 containing paints, glues and/or petroleum products and/or are located at 3p14.2 (FRA 3B), 3q21, 3q25, 3q26.2 and ionizing irradiation during a defined period of time.17,18 3q27.4 Two of the patients had breakpoints in the region of 3p14.2. Four patients had breakpoints in the region 3q21, one in addition in the region 3q25–29. All were exposed to Results mutagens (Table 3, Figure 1). Chromosome analysis Exposure to environmental factors and cancer Numerical aberrations: Four patients had clonal chromo- treatments some aberrations of the bone marrow cells including trisomy 3 in combination with other numerical and/or structural aber- rations (Table 2). Two of them had additionally an extra chro- All nine patients with monosomy 3 or structural aberrations mosome 8, the third patient had r(X), t(7;15)(q36;q22), and of chromosome 3 were exposed either to organic solvents, the fourth had −Y, del(17)(q23). Three patients had monosomy petroleum products, ionizing radiation, or antineoplastic 3, one as a single aberration, one in combination with varying agents (Table 3).
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