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

Home , Chromosome 3

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 karyotypes, but in two patients, the abnormalities appeared as single 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 arabinoside + 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 certain regions, 3p14–21, 3q21 and 3q26, in leukemias as well Cytogenetics as in other malignant diseases, suggesting that these aberrations 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 Mutagen exposures and chromosome 3 aberrations in AML R Lindquist et al 113 VP + AMSA + CYT + AMSA/DR- + VP16 LANVIS + CYT CYT CYT CYT/POCAL + + + + + DNA/NOVANTRONE DR DNA + 642 a + 100 52 0 0 (refused) 22 0 CYT 72 0 HIDAC 20 0 DR 16 0 HICAC 726 264 90 POCAL/ADR 190 0 DR 445 324 POCAL-DNA 586 260 POCAL- 329 96 POCAL/HIDAC 180 0 DR − − − − + + − + − − − − +

/l) (days) 9

(

/l) count cytopoiesis (days) remission for AML 9

(g/l) ( 3M272530 3 M2 106 42 86 3 M5841310 3 M2473149 3 M4602426 3 M2 109 2 15 3 M2 87 9 117 + + + + t(3;21)(q13–21;q22) add(3)(q25–29) − − − Blood values, morphological data, survival, time of remission and treatments of 13 patients with AML and chromosome 3 aberrations 60 M/38 72 F/76 t(3;8)(q13–21;p21) M1 74 2 25 68 M/55 The patient died of cancer of the ovary on day 726. Table 1 a 133 M/16 161 M/47 del(3)(p13p21) M2 80 220 36 115 M/62 del(3)(p14–21) M2 67 29 14 102 F/77 130 F/62 179 M/33 del(3)(q21) M4 79 42 16 148 M/84 t(1;3)(p36;q21) M2 90 5 105 143 F/69 del(3)(q21) M5 76 128 338 158 F/61 Patient No. Sex/Age Chrom 3 aberration FAB Hb WBC Platelet176 Dysmegakaryo- Survival Time of F/76 Treatment

Leukemia 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 diagnosis 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 aberrations (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). Among the four patients with an extra chro- multiple trisomies and monosomy 16 and one with mosome 3, only one was exposed to organic solvents. Time del(5)(q13), add(12)(p13), −15, −15, −17. of exposure varied from 10 to 40 years. Two patients were treated for cancer of the ovary prior to AML. One of them was also treated for breast cancer and her karyotype was complex Structural aberrations: Two patients showed structural 45,XX,del(3)(q21),del(5)(q15–21), −7, add(9)(q34),del(10)(q22), aberrations in the region 3p13–21 (Table 2). One of them had inv(17)(q11q25). The karyotype of the other patient was a single aberration, an interstitial deletion, del(3)(p13p21). The 45,XX,−3. Another patient was treated for thyreotoxicosis with other patient had del(3)(p14–21) in combination with radioactive iodine orally. Her karyotype was 46,XY,t(3;8) del(2)(p21), del(5)(q21) and i(11)(q10). (q13–21;p21),t(3;21)(q13–21;q22),del(7)(q31) (Tables 2 and All four patients with structural aberrations of 3q had break- 3).

Table 2 Karyotypes of 13 patients with AML and chromosome 3 aberrations

Patient No. No. of analyzed No. of abnormal Karyotypes metaphases metaphases

60 5 5 49,XY,+3,+8,+12 102 7 6 49,XX,+3,+8,+mar 130 11 11 46–47,X,r(X)[9],+3[9],t(7;15)(q36;q22)[cp11] 133 3 2 46,X,−Y,+3,del(17)(q23) 115 6 6 46,XY,del(2)(p21),del(3)(p14–21),del(5)(q21),i(11)(q10) 161 7 4 46,XY,del(3)(p13p21) 72 7 7 46,XX,t(3;8)(q13–21;p21),t(3;21)(q13–21;q22),del(7)(q31) 179 7 7 45–46,XY,del(3)(q21)[7],−5[6],−6[7],i(17)(q10)[7],+mar[7][cp7] 143 5 5 45,XX,del(3)(q21),del(5)(q15–21),−7,add(9)(q34), del(10)(q22), inv(17)(q11q25) 148 4 3 45,XY,t(1;3)(p36;q21),−2,add(3)(q25–29),del(4)(p14),add(11)(q23–25) 68 7 7 42–59,XY,+1[3],−3[7],+7[3],+8[4],+9[3],+10[3],+11[2],+12[3], +13[2], +14[3],+15[4],−16[3],+17[2],+19[3],+20[2],+22[2],+mar[2],[cp7] 158 4 4 45,XX,−3 176 6 6 42,XX,−3,del(5)(q13),add(12)(p13),−15,−15,−17

Leukemia Mutagen exposures and chromosome 3 aberrations in AML R Lindquist et al 115 Table 3 Occupations and treatments with antineoplastic agents, irradiation and folic acid antagonistsa in 13 patients with clonal chromosome 3 aberrations

Patient Occupation Chrom. 3 aberration Exposure Time of Time from No. exposure end of (years) exposure (years)

60 cook +3 frying fumesa (18a)(0a) 102 housewife +30 —— 130 bookbinder, shoe worker, +3 organic solvents, wolfram 40 0 bulb manufacturer 133 school boy +30 00 115 metal worker del(3)(p14–21) chromium, organic solvents 40 0 161 typographer del(3)(p13p21) organic solvents 11 0 72 manager of pensioners’ t(3;8)(q13–21;p21), sulfasalazina (colitis) (1a)(8a) home t(3;21)(q13–21;q22) radioactive iodine (thyreotoxicosis) — 12 phenantoina (epilepsy) (2a)(0a) 179 woodsman del(3)(q21) gasoline, diesel, motor exhaust 10 0 143 clerk del(3)(q21) radiation, melphalan (cancer ovary — 2 and mammae) 148 mechanic/engine-man t(1;3)(p36;q21), machine-oil, grease, paint, fuel 40 20 add(3)(q25–29) 68 storeman plastic products −3 organic solvents, plastic products 20 0 158 housewife −3 radiation, melphalan (cancer ovary) — 5 176 bookbinder −3 organic solvents Ͼ10 10 aNot settled as leukemogenic agent.

Morphology and dysmegakaryocytopoiesis of inducing structural abnormalities.29,31,32 Other mitotic dis- turbances can also be induced, creating cells with numerical There was no clear correlation between the specific type of aberrations.29,33 In the human environment there are many chromosome 3 aberrations and FAB classifications. Dys- other sources, apart from benzene, of phenols and quinones. megakaryocytopoiesis was present in four patients, one with These compounds are present in coffee, cigarette smoke, food monosomy 3 and three with breakpoints at 3q21, in one of constituents, pharmaceutical preparations, skin lotions, lip them in combination with a breakpoint in the region 3q25–29. balms and in photographic developer and may have etiologic importance for the development of a fraction of the acute leukemias.31,32 The high frequency of mutagen exposures in our Prognosis patients indicates chromosome 3 as a possible target for these compounds. AML with monosomy 3 and structural aberrations of chromo- Fragility of certain regions in the genome are suggested as some 3 were associated with poor prognosis. Only two of nine targets for mutagen attacks with the creation of chromosome patients entered remission, which lasted 90 days for one aged breaks and translocations.34–37 For example, benzene was 47 years and 96 days for one aged 33. The patients with tri- shown to be a potent inducer of chromatide breaks at the frag- somy 3 had longer times of remission (324 days, 642 days ile sites 3p14.2, 3q21, 3q25, 3q26.2 and 3q27.38 These fragile (death because of carcinoma of the ovary post-leukemia) and regions were suggested as targets of mutagens that could 260 days). One patient died on admission day without cause chromosome abnormalities and furthermore to induce being treated. leukemia and lymphoma.39 Two of our patients who were exposed to organic solvents containing benzene had chromosome breakpoints in the region of the fragile site 3p14.2, a Discussion site especially prone to show aberrations after exposure to benzene according to in vitro studies by Yunis et al.38 All patients with structural abnormalities of chromosome 3 or Shi et al40 noted a relationship between 3p aberrations and monosomy 3 had been occupationally exposed to organic sol- treatment-related AML, finding that two out of 11 patients with vents and/or petroleum products, or had therapeutic 3p21 aberration had secondary acute leukemia. Johansson et irradiation, antineoplastic drugs or radioactive iodine (Table al41 found that 3p deletions were more common in treatment- 3). An increased risk of acute leukemia has previously been related AML than in de novo AML. Other studies lend support shown for people with occupational exposure to organic sol- for the view that targeting of the fragile site FRA3B at 3p14.2 vents14,17,27 and petroleum products, such as gasoline or may be of importance in other types of cancer such as in diesel fuels and motor exhausts.15,16,18,28 Benzene, an aro- cancer of the lung del(3)(p14p23),42,43 in kidney cancer matic solvent, a constituent of organic solvents and lead-free 3p14.2,44–46 in breast cancer del(3)(p12p14),2,3,47 and in can- gasoline is considered to be an important leukemogenic cer of the ovary 3p13–21.48 It was suggested that cancer- agent.14,27,29,30 Benzene is metabolized by cytochrome 450 specific deletions at the FRA3B region (3p14.2) derived from 2E1 to phenol and hydrochinone, catechol and muconic breaks in fragile sites within the FHIT gene recently located to acid.31,32 It has been suggested that quinones and related free this region.49 Although FHIT has been implicated as a cancer radicals are the ultimate toxic metabolites of benzene exhibit- suppressor gene, this has still not been proven.50 Sequence ing their effects on topoisomerase II and on DNA thus capable analysis of 276 kb of the FRA3B/FHIT locus and 22 associated

Leukemia Mutagen exposures and chromosome 3 aberrations in AML R Lindquist et al 116

Figure 1 Chromosome 3. The localizations of the FHIT gene, the regions of aberration in dysmegakaryocytopoiesis, the EVI1 gene, the MDS1 gene and the thrombopoietin gene, the common fragile sites and the regions of structural aberrations of chromosome 3 in 13 patients with AML.

cancer cell deletion-endpoints shows that this locus is ‘a fre- mality at 3q21, a breakpoint at 3q25–29. In this region 3q26, quent target of homologous recombination between long there are two genes: MDS 1 and EVI 1 (Figure 1). They have interspersed unclear element sequences resulting in FHIT gene been implicated in acute myeloid leukemia.63,64 The internal deletions, probably as a result of carcinogen-induced t(3;21)(q26;q22) is a recurring abnormality in therapy-related damage of FRA3B fragile sites’.49 This association was con- acute myeloid leukemia and myelodysplastic syndrome.65 firmed in lung cancer,51 breast cancer,52 gastric cancer,53 These findings also suggest that this region is of importance pancreatic cancer54 and myeloid leukemia.55 for mutagenic attacks. Four of our patients had breakpoints in the fragile site- All patients with chromosome 3 aberrations but one with region 3q21. They were exposed to iodine-131, radiation and monosomy 3 and one with del(3)(p13p21), had complex kary- antineoplastic agents, petroleum products and organic sol- otypes with involvement of chromosomes known to be abnor- vents, respectively (Table 3). The exposure to radioactive iod- mal in secondary leukemias (s-AML) and present after radi- ine has previously been reported to be associated with the ation and cytostatic treatments.12,40,57,65,66 Exposure to development of leukemia.56 Alimena et al57 published a case environmental mutagens as well as mutagenic treatments pre- of acute leukemia secondary to treatment with alkylating ceded the development of AML. Thus the finding of complex agents and topoisomerase II inhibitors with the aberration karyotypes of occupationally exposed patients provides dup(3)(q21q26). Thus, these results support the view that further support for the view that exposure is important for the mutagen targeting on fragile sites also to the chromosome etiology of the disease. Fragile sites could be preferential sites region 3q21 may explain the association between the of mutagen interaction with the chromosomes, but the malig- mutagens, the observed aberrations in the 3q21 region and nant transformation as a result of this interaction is also depen- leukemia. dent on other factors such as the presence of regulatory genes The specific syndrome of dysmegakaryocytopoiesis has pre- of the cell in these loci.67 viously been described in patients with a breakpoint at 3q21 Thus, although our results indicate an importance of fragile or an inversion 3 (q21q26) in both AML,7 CML,8,9 and site regions as targets for mutagens and therefore for the devel- MDS,10,11,58 which is frequently associated with monosomy 7, opment of leukemia, some controversies still remain as to the abnormal thrombopoiesis and poor prognosis.9,58,59 Cases role of fragile site in the development of cancer.68–70 with only one of these breakpoints may have milder features of the syndrome. Dysmegakaryocytopoiesis was found in four of our patients. Three of them had structural aberrations at Acknowledgements 3q21 (one was combined with an abnormality at 3q25–29) and one had monosomy 3. In one patient (No. 143) with This work was supported by grants from the Swedish Work t(AML), del(3)(q21) was combined with −7 and other abnor- Environmental Fund, The Swedish Cancer Fund and the Karol- malities (Tables 1 and 2). Thus, our results confirm earlier inska Institutet’s Funds. reports on the association of dysmegakaryocytopoiesis and structural changes at the regions 3q21 and 3q26. The throm- References bopoietin gene is located on chromosome 3q26.33–q27.60 It 61,62 is probably not activated in the 3q21q26 syndrome. 1 Devald G. Fourth International Workshop on Chromosomes in One of our exposed patients had, in addition to an abnor- Leukemia 1982: abnormalities of chromosome 3 among 24

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