Mutagen exposures and chromosome 3 aberrations in acute ... - Nature

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 ¨ st2 and G Gahrton1 R Lindquist1, AM Forsblom1, Å O 1

Department 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 with clonal aberrations involving chromosome 3 were studied. Three patients had monosomy 3, four had trisomy 3, and six had structural aberrations of chromosome 3. In the majority of 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) and the other as monosomy 3. All breakpoints of chromosome 3 were found in the fragile site regions 3p14.2, 3q21 and 3q26– 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 to organic solvents and/or petroleum products or treatments with irradiation or antineoplastic agents. The association among mutagen exposure, structural chromosome 3 aberrations and fragile sites in AML may indicate that targeting of the mutagens to these sites is of importance for the etiology of the disease. Leukemia (2000) 14, 112–118. Keywords: acute myeloid leukemia; chromosomes 3; chromosome, fragile site; occupational exposure; megakaryocyte; mutagen exposure

Introduction Structural and numerical aberrations of chromosome 3 have been identified in hematological diseases1 as well as in other human malignancies.2,3 In acute myelocytic leukemia (AML), reports at the Fourth International Workshop on Chromosomes in Leukaemia found that 3% of the patients with AML 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 as in other malignant diseases, suggesting that these aberrations are non-random events important for the development of the malignancy.2–4 Previous studies indicated an association between structural aberrations in the regions 3q21 and 3q26 and dysmegakaryocytopoiesis in leukemias of different types such as AML,5–7 chronic myelocytic leukemia (CML)8,9 and myelodysplastic syndrome (MDS).10,11 Pedersen-Bjergaard et al12 have shown that chromosome 3 aberrations are frequently present in therapy-related, secondary AML (t-AML) after treatments with irradiation and/or antineoplastic agents. Both balanced translocations involving 3q26 and 11q23 or 21q22, and deletions of chromosome 3 were observed. Molecular studies have shown that the region 3q21 harbors 10 different breakpoints in leukemia. These are combined with reciprocal translocations with other chromosomes such as 1, 5, 11, 12 and 15.13 Studies of exposures to organic solvents or petroleum products have indicated an association with the development of leukemia.14–18 The aim of the present study was to analyze whether AML patients with chromosome 3 aberrations may

have had such exposures or other exposures of mutagens such as previous therapies with antineoplastic agents and/or radiation. Materials and methods

Patients Thirteen patients with AML and chromosome 3 aberrations were investigated; six males and seven females. The median age was 62 years (range 16–84) (Table 1). The patients participated in prospective treatment studies within the Leukemia Group of Middle Sweden (LGMS).19,20 Almost all patients with leukemia in this region are admitted to LGMS hospitals and enter co-operative treatment protocols. The study was approved by ethical committee of the Huddinge University Hospital, Karolinska Institutet. The patients in the range of 16–60 years of age were given courses of drug combinations in randomized studies as follows: (1) POCAL (prednisolone + vincristine + cytosine arabinoside + adriamycin + thioguanine) or (2) POCAL-DNA (POCAL with adriamycin bound to DNA) or (3) DR (daunorubicin) + CYT (cytosine arabinoside).19,20 The elderly patients (⬎60 years) were treated with (1) DR + CYT or with (2) CYT or with (3) HIDAC (high-dose cytosine arabinoside) (Table 1).

Cytogenetics Bone marrow samples for chromosome analysis were taken at diagnosis before cytostatic drug treatments. Bone marrow cells were analyzed both by direct method21 and by in vitro culture for 24 h without mitogen. Peripheral blood cells were incubated for 48–72 h both with and without phytohemagglutinin (PHA) (Burroughs, Wellcome, UK) in RPMI medium with 10% calf serum as nutrient medium for bone marrow. For peripheral blood the patients own sera were used. For 2 h before harvesting, the cells were exposed to colchicine to a final concentration of 0.005 ␮g/ml (Sigma, St Louis, MO, USA) for bone marrow and 0.05 ␮g/ml for blood. Hypotonic treatment with potassium chloride solution 0.075 M was done before cell fixation with a mixture of 1:3 glacial acetic acid and of 100% methyl alcohol. The conventional Q-banding technique ad modum Caspersson22 was used for chromosome staining and the International System for Human Cytogenetic Nomenclature (1995) was used for chromosome classification.23

Morphology Correspondence: R Lindquist, Department of Hematology, Huddinge University Hospital, SE 141 86 Huddinge, Sweden; Fax: (+)46 (8) 58 58 25 25 Received 30 March 1999; accepted 14 September 1999

All bone marrow and blood samples were analyzed by the ¨ ), without knowledge of the results of same investigator (ÅO the chromosome analyses. The diagnostic procedures were

M/62 M/47 F/76

M/33 F/69

M/84

M/55 F/61 F/76

115 161 72

179 143

148

68 158 176

t(1;3)(p36;q21) add(3)(q25–29) −3 −3 −3

del(3)(p14–21) del(3)(p13p21) t(3;8)(q13–21;p21) t(3;21)(q13–21;q22) del(3)(q21) del(3)(q21)

+3 +3 +3 +3

Chrom 3 aberration

The patient died of cancer of the ovary on day 726.

a

M/38 F/77 F/62 M/16

Sex/Age

M4 M2 M2

M2

M4 M5

M2 M2 M1

M2 M5 M2 M2

FAB

60 109 87

90

79 76

67 80 74

72 84 47 106

Hb (g/l)

24 2 9

5

42 128

29 220 2

5 13 31 42

WBC (×109/l)

26 15 117

105

16 338

14 36 25

30 10 49 86

Platelet count (×109/l) 445 1 726+a 586 190 264 22 329 72 52 20 16 180

− − − + + + − − +

Survival (days)

− − − −

Dysmegakaryocytopoiesis

0 0 0

0

96 0

0 90 0

324 0 642+ 260

Time of remission (days)

Blood values, morphological data, survival, time of remission and treatments of 13 patients with AML and chromosome 3 aberrations

60 102 130 133

Patient No.

Table 1

DR+CYT HICAC DR+CYT/POCAL

POCAL/HIDAC+AMSA HIDAC+AMSA/DRDNA+VP16 0 (refused)

POCAL-DNA 0 DR+CYT POCALDNA/NOVANTRONE DR+CYT POCAL/ADR+CYT+VP CYT+LANVIS

Treatment for AML

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

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114

based on morphological methods. The French–American– British (FAB) classification of the leukemias was used as pro¨ st posed by Bennett et al,24,25 with the slight modification of O et al.26 Dysmegakaryocytopoiesis was defined as an abnormal disturbed thrombocytopoiesis and/or reduction in the number of megakaryocytes as well as the presence of cytological abnormal megakaryocytes, especially hypolobulated, small megakaryocytes in the bone marrow. The CD61 antibody was not used in the analysis.

points in the region 3q21 as part of complex karyotypes. One patient had a breakpoint at 3q13–21 with two translocations of chromosomes 8 and 21, t(3;8)(q13–21;p21), and t(3;21)(q13–21;q22) and in addition del(7)(q31). Two patients had del(3)(q21) and both of them abnormalities involving chromosomes 5 and 17. One patient had t(1;3)(p36;q21) and add(3)(q25–29). Five patients had involvements of chromosomes 3 and 17. 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 were used as sources of information concerning occupational 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 solventcontaining paints, glues and/or petroleum products and/or ionizing irradiation during a defined period of time.17,18 Results

Chromosome 3 breakpoints and constitutive fragile sites Constitutive or common fragile sites (c-fra) on chromosome 3 are located at 3p14.2 (FRA 3B), 3q21, 3q25, 3q26.2 and 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 mutagens (Table 3, Figure 1).

Chromosome analysis Numerical aberrations: Four patients had clonal chromosome 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 chromosome 8, the third patient had r(X), t(7;15)(q36;q22), and the fourth had −Y, del(17)(q23). Three patients had monosomy 3, one as a single aberration, one in combination with varying multiple trisomies and monosomy 16 and one with del(5)(q13), add(12)(p13), −15, −15, −17. Structural aberrations: Two patients showed structural aberrations in the region 3p13–21 (Table 2). One of them had a single aberration, an interstitial deletion, del(3)(p13p21). The other patient had del(3)(p14–21) in combination with del(2)(p21), del(5)(q21) and i(11)(q10). All four patients with structural aberrations of 3q had breakTable 2

Patient No.

Leukemia

Exposure to environmental factors and cancer treatments All nine patients with monosomy 3 or structural aberrations of chromosome 3 were exposed either to organic solvents, petroleum products, ionizing radiation, or antineoplastic agents (Table 3). Among the four patients with an extra chromosome 3, only one was exposed to organic solvents. Time 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 45,XX,del(3)(q21),del(5)(q15–21), −7, add(9)(q34),del(10)(q22), inv(17)(q11q25). The karyotype of the other patient was 45,XX,−3. Another patient was treated for thyreotoxicosis with radioactive iodine orally. Her karyotype was 46,XY,t(3;8) (q13–21;p21),t(3;21)(q13–21;q22),del(7)(q31) (Tables 2 and 3).

Karyotypes of 13 patients with AML and chromosome 3 aberrations

No. of analyzed metaphases

No. of abnormal metaphases

60 102 130 133 115 161 72 179 143 148 68

5 7 11 3 6 7 7 7 5 4 7

5 6 11 2 6 4 7 7 5 3 7

158 176

4 6

4 6

Karyotypes

49,XY,+3,+8,+12 49,XX,+3,+8,+mar 46–47,X,r(X)[9],+3[9],t(7;15)(q36;q22)[cp11] 46,X,−Y,+3,del(17)(q23) 46,XY,del(2)(p21),del(3)(p14–21),del(5)(q21),i(11)(q10) 46,XY,del(3)(p13p21) 46,XX,t(3;8)(q13–21;p21),t(3;21)(q13–21;q22),del(7)(q31) 45–46,XY,del(3)(q21)[7],−5[6],−6[7],i(17)(q10)[7],+mar[7][cp7] 45,XX,del(3)(q21),del(5)(q15–21),−7,add(9)(q34), del(10)(q22), inv(17)(q11q25) 45,XY,t(1;3)(p36;q21),−2,add(3)(q25–29),del(4)(p14),add(11)(q23–25) 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] 45,XX,−3 42,XX,−3,del(5)(q13),add(12)(p13),−15,−15,−17


Table 3 Occupations and treatments with antineoplastic agents, irradiation and folic acid antagonistsa in 13 patients with clonal chromosome 3 aberrations

Patient No.

Occupation

Chrom. 3 aberration

Exposure

cook housewife bookbinder, shoe worker, bulb manufacturer school boy metal worker typographer manager of pensioners’ home

+3 +3 +3

frying fumesa 0 organic solvents, wolfram

+3 del(3)(p14–21) del(3)(p13p21) t(3;8)(q13–21;p21), t(3;21)(q13–21;q22)

179 143

woodsman clerk

del(3)(q21) del(3)(q21)

148

mechanic/engine-man

68 158 176

storeman plastic products housewife bookbinder

t(1;3)(p36;q21), add(3)(q25–29) −3 −3 −3

0 chromium, organic solvents organic solvents sulfasalazina (colitis) radioactive iodine (thyreotoxicosis) phenantoina (epilepsy) gasoline, diesel, motor exhaust 10 radiation, melphalan (cancer ovary and mammae) machine-oil, grease, paint, fuel 40

60 102 130 133 115 161 72

organic solvents, plastic products radiation, melphalan (cancer ovary) organic solvents

Time of exposure (years)

115

Time from end of exposure (years)

(18a) — 40

(0a) — 0

0 40 11 (1a) — (2a) 0 —

0 0 0 (8a) 12 (0a) 2

20 20 — ⬎10

0 5 10

a

Not settled as leukemogenic agent.

Morphology and dysmegakaryocytopoiesis There was no clear correlation between the specific type of chromosome 3 aberrations and FAB classifications. Dysmegakaryocytopoiesis was present in four patients, one with monosomy 3 and three with breakpoints at 3q21, in one of them in combination with a breakpoint in the region 3q25–29.

Prognosis AML with monosomy 3 and structural aberrations of chromosome 3 were associated with poor prognosis. Only two of nine patients entered remission, which lasted 90 days for one aged 47 years and 96 days for one aged 33. The patients with trisomy 3 had longer times of remission (324 days, 642 days (death because of carcinoma of the ovary post-leukemia) and 260 days). One patient died on admission day without being treated. Discussion All patients with structural abnormalities of chromosome 3 or monosomy 3 had been occupationally exposed to organic solvents and/or petroleum products, or had therapeutic irradiation, antineoplastic drugs or radioactive iodine (Table 3). An increased risk of acute leukemia has previously been shown for people with occupational exposure to organic solvents14,17,27 and petroleum products, such as gasoline or diesel fuels and motor exhausts.15,16,18,28 Benzene, an aromatic solvent, a constituent of organic solvents and lead-free gasoline is considered to be an important leukemogenic agent.14,27,29,30 Benzene is metabolized by cytochrome 450 2E1 to phenol and hydrochinone, catechol and muconic acid.31,32 It has been suggested that quinones and related free radicals are the ultimate toxic metabolites of benzene exhibiting their effects on topoisomerase II and on DNA thus capable

of inducing structural abnormalities.29,31,32 Other mitotic disturbances can also be induced, creating cells with numerical aberrations.29,33 In the human environment there are many other sources, apart from benzene, of phenols and quinones. These compounds are present in coffee, cigarette smoke, food constituents, pharmaceutical preparations, skin lotions, lip 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 patients indicates chromosome 3 as a possible target for these compounds. Fragility of certain regions in the genome are suggested as targets for mutagen attacks with the creation of chromosome breaks and translocations.34–37 For example, benzene was shown to be a potent inducer of chromatide breaks at the fragile sites 3p14.2, 3q21, 3q25, 3q26.2 and 3q27.38 These fragile regions were suggested as targets of mutagens that could cause chromosome abnormalities and furthermore to induce 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 site especially prone to show aberrations after exposure to benzene according to in vitro studies by Yunis et al.38 Shi et al40 noted a relationship between 3p aberrations and treatment-related AML, finding that two out of 11 patients with 3p21 aberration had secondary acute leukemia. Johansson et al41 found that 3p deletions were more common in treatmentrelated AML than in de novo AML. Other studies lend support for the view that targeting of the fragile site FRA3B at 3p14.2 may be of importance in other types of cancer such as in cancer of the lung del(3)(p14p23),42,43 in kidney cancer 3p14.2,44–46 in breast cancer del(3)(p12p14),2,3,47 and in cancer of the ovary 3p13–21.48 It was suggested that cancerspecific deletions at the FRA3B region (3p14.2) derived from breaks in fragile sites within the FHIT gene recently located to this region.49 Although FHIT has been implicated as a cancer suppressor gene, this has still not been proven.50 Sequence analysis of 276 kb of the FRA3B/FHIT locus and 22 associated Leukemia


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 frequent target of homologous recombination between long interspersed unclear element sequences resulting in FHIT gene internal deletions, probably as a result of carcinogen-induced damage of FRA3B fragile sites’.49 This association was confirmed in lung cancer,51 breast cancer,52 gastric cancer,53 pancreatic cancer54 and myeloid leukemia.55 Four of our patients had breakpoints in the fragile siteregion 3q21. They were exposed to iodine-131, radiation and antineoplastic agents, petroleum products and organic solvents, respectively (Table 3). The exposure to radioactive iodine has previously been reported to be associated with the development of leukemia.56 Alimena et al57 published a case of acute leukemia secondary to treatment with alkylating agents and topoisomerase II inhibitors with the aberration dup(3)(q21q26). Thus, these results support the view that mutagen targeting on fragile sites also to the chromosome region 3q21 may explain the association between the mutagens, the observed aberrations in the 3q21 region and leukemia. The specific syndrome of dysmegakaryocytopoiesis has previously been described in patients with a breakpoint at 3q21 or an inversion 3 (q21q26) in both AML,7 CML,8,9 and MDS,10,11,58 which is frequently associated with monosomy 7, abnormal thrombopoiesis and poor prognosis.9,58,59 Cases 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 3q21 (one was combined with an abnormality at 3q25–29) and one had monosomy 3. In one patient (No. 143) with t(AML), del(3)(q21) was combined with −7 and other abnormalities (Tables 1 and 2). Thus, our results confirm earlier reports on the association of dysmegakaryocytopoiesis and structural changes at the regions 3q21 and 3q26. The thrombopoietin gene is located on chromosome 3q26.33–q27.60 It is probably not activated in the 3q21q26 syndrome.61,62 One of our exposed patients had, in addition to an abnorLeukemia

mality at 3q21, a breakpoint at 3q25–29. In this region 3q26, there are two genes: MDS 1 and EVI 1 (Figure 1). They have been implicated in acute myeloid leukemia.63,64 The t(3;21)(q26;q22) is a recurring abnormality in therapy-related acute myeloid leukemia and myelodysplastic syndrome.65 These findings also suggest that this region is of importance for mutagenic attacks. All patients with chromosome 3 aberrations but one with monosomy 3 and one with del(3)(p13p21), had complex karyotypes with involvement of chromosomes known to be abnormal in secondary leukemias (s-AML) and present after radiation and cytostatic treatments.12,40,57,65,66 Exposure to environmental mutagens as well as mutagenic treatments preceded the development of AML. Thus the finding of complex karyotypes of occupationally exposed patients provides further support for the view that exposure is important for the etiology of the disease. Fragile sites could be preferential sites of mutagen interaction with the chromosomes, but the malignant transformation as a result of this interaction is also dependent on other factors such as the presence of regulatory genes of the cell in these loci.67 Thus, although our results indicate an importance of fragile site regions as targets for mutagens and therefore for the development of leukemia, some controversies still remain as to the role of fragile site in the development of cancer.68–70 Acknowledgements This work was supported by grants from the Swedish Work Environmental Fund, The Swedish Cancer Fund and the Karolinska Institutet’s Funds. References 1 Devald G. Fourth International Workshop on Chromosomes in Leukemia 1982: abnormalities of chromosome 3 among 24


2 3 4 5 6

7 8

9

10 11 12

13 14

15

16

17 18 19

patients with de novo ANLL. Cancer Genet Cytogenet 1984; 11: 306. Mitelman F. Chromosomes 1–12. Catalog of Chromosome Aberrations in Cancer, 5th edn. Wiley-Liss: New York, 1994, pp 439–489. Heim S, Mitelman F. Chromosomal and molecular genetic aberrations of tumor cells. Cancer Cytogenetics, 2nd edn. Alan R Liss: New York, 1995, pp 69–140. Smith DI, Glover TW, Gemmill R, Drabkin H, O’Connell P, Naylor SL. Report of the Fifth International Workshop on Human Chromosome 3 mapping 1994. Cytogenet Cell Genet 1995; 68: 125–136. Sweet DL. Acute myelocytic leukemia and thrombocythemia associated with an abnormality of chromosome No. 3. Cancer Genet Cytogenet 1979; 1: 33–37. Bernstein R, Pinto MR, Behr A, Medelow B. Chromosome 3 abnormalities in acute nonlymphocytic leukemia (ANLL) with abnormal thrombopoiesis: reports of three patients with a ‘new’ inversion anomaly and a further case of homologous translocation. Blood 1982; 60: 613–617. Mecucci C, Van Den Berghe H. Thrombocytosis and inv(3)(q21q26). Blood 1983; 61: 1027. Carbonell F, Hoelzer D, Thiel E, Bartle R. Ph1-positive CML associated with megakaryocytic hyperplasia and thrombocythemia and an abnormality of chromosome no. 3. Cancer Genet Cytogenet 1982; 6: 153–161. Bernstein R, Bagg A, Pinto M, Lewis D, Mendelow B. Chromosome 3q21 abnormalities associated with hyperactive thrombopoiesis in acute blastic transformation of chronic myeloid leukemia. Blood 1986; 68: 652–657. Mertens F, Johansson B, Billstro¨m R, Engquist L, Mitelman F. A case of myelodysplastic syndrome with high platelet counts and a t(3;8)(q26;q24). Cancer Genet Cytogenet 1987; 27: 1–4. Norrby A, Riddell B, Swolin B, Westin J. Rearrangement of chromosome No. 3 in a case of preleukemia with thrombocytosis. Cancer Genet Cytogenet 1981; 5: 257–263. Pedersen-Bjergaard J, Pedersen M, Roulstow D, Philip P. Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. Blood 1995; 86: 3542–3552. Rynditch A, Pekarsky Y, Snittger S, Gardiner K, Leukemia breakpoint region in 3q21 is gene rich. Gene 1997; 193: 49–57. International Agency for Research on Cancer (IARC). On the evaluation of carcinogenic risks to humans: some organic solvents, resin monomers and related compounds, pigments and occupational exposures in paint manufacture and painting. Some petroleum solvents. 1989; 47: 43–77. Occupational exposures in paint manufacture and painting 1989; 47: 329–442. World Health Organization (WHO): Lyon, France. International Agency for Research on Cancer (IARC). On the evaluation of carcinogenic risks to humans: Diesel and gasoline engine exhausts and some nitroarenes. Diesel and gasoline engine exhausts. 1989; 46: 41–185. World Health Organization (WHO): Lyon, France. International Agency for Research on Cancer (IARC). On the evaluation of carcinogenic risks to humans: Occupational exposures in petroleum refining; Crude oil and major petroleum fuels. General remarks. 1989; 45: 31–36. Gasoline. 1989; 45: 159–201. Diesel fuels. 1989; 45: 219–237. World Health Organization (WHO): Lyon, France. Lindquist R, Nilsson B, Eklund G, Gahrton G. Increased risk of developing acute leukemia after employment as a painter. Cancer 1987; 60: 1378–1384. Lindquist R, Nilsson B, Gahrton G, Eklund G. Acute leukemia and exposure to petroleum products in drivers. Eur J Hematol 1991; 47: 98–103. Paul C, Bjo¨rkholm M, Christenson I, Engstedt L, Gahrton G, Johansson B, Ja¨rnmark M, Killander A, Lindemalm C, Lindquist R, Lockner D, Lo¨nnkvist B, Mellstedt H, Merk K, Palmblad J, Peterson C, Simonsson B, Stalfelt A-M, Sundstro¨m C, Wadman B, Wedelin ¨ berg G, O ¨ st A. Induction and intensive C, Ude´n A-M, Ahre A, O consolidation in acute nonlymphoblastic leukemia (ANLL) with combinations containing doxorubicin-DNA. Prolonged remission duration and survival. In: Lectures and Symposia 14th International Cancer Congress, Budapest. Eckhardt L (ed). Biological response modifiers. Leuk Lymphomas 1986; 10: 101–108.

20 Paul C, Tidefelt U, Gahrton G, Bjo¨rkholm M, Ja¨rnmark M, Killander A, Kimby E, Liliemark E, Liliemark J, Lindeberg A, Lindquist R, Lockner D, Lo¨nnqvist B, Mellstedt H, Merk K, Palmblad J, Peterson C, Simonsson B, Stalfelt A-M, Sundstro¨m C, Wadman B, Wed¨ berg G, O ¨ st A. A randomized comparison elin C, Ude´n A-M, O of doxorubicin and doxorubicin-DNA in the treatment of acute nonlymphoblastic leukemia. Leuk Lymphoma 1991; 3: 355–364. 21 Tjou JH, Wang J. Chromosome preparations of bone marrow cells without prior in vitro culture or in vivo colchicine administration. Stain Technol 1962; 37: 17–20. 22 Caspersson T, Lomakka G, Zech L. The fluorescence patterns of the human metaphase chromosome – distinguishing characters and variability. Hereditas 1971; 67: 89–102. 23 ISCN. An International System for Human Cytogenetic Nomenclature. Mitelman F (ed). S Karger: Basel, 1995. 24 Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C. Proposals for the classification of the acute leukemias. Br J Haematol 1976; 44: 451–458. 25 Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C. Criteria for the diagnosis of acute leukemia of megakaryocytic lineage (M7). Ann Intern Med 1985; 103: 460–462. ¨ st Å, Lagerlo¨f B, Sundstro¨m C. A study of reproducibility of the 26 O diagnostic criteria for acute leukemia. Scand J Haematol 1983; 31: 257–266. 27 Infante PF, Rinsky RA, Wagoner JK, Young RJ. Leukemia in benzene workers. Lancet 1977; 2: 76–78. 28 Brandt L, Nilsson PG, Mitelman F. Occupational exposure to petroleum products in men with acute nonlymphocytic leukemia. Br Med J 1978; 4: 553. 29 International Programme on Chemical Safety (IPCS). World Health Organization (WHO), Geneva. Environmental Health Criteria. 150. Benzene. Ed. EE McConnell Summary and conclusions. 1993 pp 13–8. Sources of human and environmental exposure. pp 28–31. 30 Smith MT. The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. Environ Health Perspect 1996; 104: 1219–1226. 31 Smith MT, Fanning EW. Report on the workshop entitled: ‘Modeling chemically induced leukemia – implications for benzene risk assessment.’ Leukemia Res 1997; 21: 361–374. 32 Snyder R, Hedli CC. An overview of benzene metabolism. Environ Health Perspect 1996; 104: 1165–1171. 33 Oshimura M, Barrett JC. Chemically induced aneuploidy in mammalian cells: mechanisms and biological significance in cancer. Environ Mutagen 1986; 8: 129–159. 34 Dekaban A. Persisting clone of cells with an abnormal chromosome in a woman previously irradiated. J Nucl Med 1965; 6: 740–746. 35 Sutherland GR. Fragile sites on human chromosomes: demonstrations of their dependence on the type of tissue culture medium. Science 1977; 197: 265–266. 36 Sutherland GR. Heritable fragile sites on human chromosomes II. Distribution, phenotypic effects and cytogenetics. Am J Hum Genet 1979; 31: 136–148. 37 Yunis JJ, Soreng AC. Constitutional fragile sites and cancer. Science 1984; 226: 1099–1204. 38 Yunis J, Soreng AL, Bove A. Fragile sites are targets of diverse mutagens and carcinogens. Oncogene 1987; 1: 59–69. 39 Yunis JJ. Fragile sites and predisposition to leukemia and lymphoma. Cancer Genet Cytogenet 1984; 12: 85–88. 40 Shi G, Weh HJ, Martensen S, Seeger D, Hossfeld DK. 3p21 is a recurrent treatment-related breakpoint in myelodysplastic syndrome and acute myeloid leukemia. Cytogenet Cell Genet 1996; 74: 295–299. 41 Johansson B, Billstro¨m R, Kristoffersson U, Akerman M, Garwicz S, Ahlgren T, Malm C, Mitelman F. Deletion of chromosome arm 3p in hematologic malignancies. Leukemia 1997; 11: 1207–1213. 42 Whang-Peng J, Kao-Shan CS, Lee ED. Specific chromosome defect associated with human small cell lung cancer. Deletion 3p(14– 23). Science 1982; 215: 181–182. 43 Kok K, Osinga J, Carritt B, Davis MB, van der Hout AH, van der Veen AY, Landsvater RM, de Leij LFMH, Berendsen HH, Postmus PE, Poppema S, Buys CHCM. Deletion of a DNA sequence at the

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118 44

45

46

47 48 49

50 51

52

53 54

55 56

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chromosomal region 3p21 in all major types of lung cancer. Nature 1987; 330: 578–581. Drabkin HA, Bradley C, Hart I, Bleskan J, Li FP, Patterson D. Translocation of c-myc in the hereditary renal cell carcinoma associated with a t(3;8)(p14.2;q24.13) chromosomal translocation. Proc Natl Acad Sci USA 1985; 82: 6980–6984. Teyssier JR, Hemry I, Dozier C, Ferre D, Adnet JJ, Pluot M. Recurrent deletion of the short arm of chromosome 3 in human renal cell carcinoma, shift of the c-raf 1 locus. J Natl Cancer Inst 1986; 77: 1187–1191. Boldog F, Arheden K, Imreh S, Strombeck B, Szekely L, Erlandsson R, Maresek Z, Sumegi J, Mitelman F, Klein G. Involvement of 3p deletions in sporadic and hereditary forms of renal cell carcinoma. Genes Chromosomes Cancer 1991; 3: 403–406. Gebhart E, Bruderlein S, Augustus M, Siebert E, Feldner J, Schmidt W. Cytogenetic studies on human breast carcinomas. Breast Cancer Res Treat 1986; 8: 125–138. Trent JM, Salmon SE. Karyotypic analysis of human ovarian carcinoma cells cloned in short term agar culture. Cancer Genet Cytogenet 1981; 3: 279–291. Inoue H, Ishii H, Alder H, Snyder E, Druck T, Huebner K, Croce CM. Sequence of the FRA3B common fragile region: implications for the mechanism of FHIT deletion. Proc Natl Acad Sci USA 1997; 94: 14584–14589. Pennisi E. New gene forges link between fragile site and many cancers. Science 1996; 272: 649. Fong KM, Bisterveld EJ, Virmani A, Wistuba I, Sekido Y, Bader SA, Ahmadian M, Ong ST, Rassool FV, Zimmerman PV, Giallone G, Gazdar AF, Minna JD. FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. Cancer Res 1997; 57: 2256–2257. Ahmadian M, Wistuba II, Fong KM, Behrens C, Kodagoda DR, Saboorian MH, Shay J, Tomlinson GE, Blum J, Minna JD, Gazdar AF. Analysis of the FHIT gene and FRA3B region in sporadic breast cancer, preneoplastic lesions, and familial breast cancer probands. Cancer Res 1997; 57: 3664–3668. Baffa R, Veronese ML, Santoro R, Mandes B, Palazzo JP, Rugge M, Santoro E, Croce CM, Huebner K. Loss of FHIT expression in gastric carcinoma. Cancer Res 1998; 58: 4708–4714. Shridhar R, Shridhar V, Wang X, Paradee W, Dugan M, Sarkar F, Wilke C, Glover TW, Vaitkevicius VK, Smith DI. Frequent breakpoints in the 3p14.2 fragile site, FRA3B, in pancreatic tumors. Cancer Res 1996; 56: 4347–4350. Sugimoto K, Yamada K. Miyagawa K, Hirai H, Oshimi K. Decreased or altered expression of the FHIT gene in human leukemias. Stem Cell 1997; 15: 223–228. Hall P, Boice JD Jr, Berg G, Bjelkengren G, Ericsson UB, Hallquist A, Lidberg M, Lundell G, Mattsson A, Tennvall J, Wiklund K, Holm L-E. Leukemia incidence after iodine-131 exposure. Lancet 1992; 340: 1–4. Alimena G, Cedrone M, Nanni M, De Cuia MR, Lo Coco F, De Sanctis V, Cimino G, Mancini M. Acute leukemia presenting a

58

59 60 61

62

63

64

65

66

67

68 69

70

variant Ph chromosome with p190 expression, dup 3q and −7, developed after malignant lymphoma treated with alkylating agents and topoisomerase II inhibitors. Leukemia 1995; 9: 1483–1486. Pintado T, Ferro MT, Sanroman C, Mayayo M, Larana JG. Clinical correlations of the 3q21;3q26 cytogenetic anomaly. A leukemic or myelodysplastic syndrome with preserved or increased platelet production and lack of response to cytotoxic drug therapy. Cancer 1985; 55: 535–541. Horsman DE, Gascoyne RD, Barnett MJ. Acute leukemia with structural rearrengments of chromosome 3. Leuk Lymphoma 1995; 16: 369–377. Battout S. Thrombopoietin. A review. Haemostasis 1997; 27: 1–8. Suzukawa K, Satoh H, Taniwaki M, Yokota J, Morishita K. The human thrombopoietin gene is located on chromosome 3q26.33– q27, but is not transcriptionally activated in leukemia cells with 3q21 and 3q26 abnormalities (3q21q26 syndrome). Leukemia 1995; 9: 1328–1331. Bouscary D, Fontenay-Roupie M, Chretien S, Hardy AC, Viguie F, Picard F, Melle J, Dreyfus F. Thrombopoietin is not responsible for the thrombocytosis observed in patients with acute myeloid leukemias and the 3q21q26 syndrome. Br J Haematol 1995; 91: 425–427. Fichelson S, Dreyfus F, Berger R, Melle J, Bastard C, Miclea JM, Gisselbrecht S. EVI-1 expression in leukemic patients with rearrangements of the 3q25–q28 chromosomal region. Leukemia 1992; 6: 93–99. Morishita K, Parganas E, William CL, Whittaker MH, Drabkin H, Oval J, Taetle R, Valentine MB, Ihle JN. Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300–400 kilobases on chromosome band 3q26. Proc Natl Acad Sci USA 1992; 89: 3937–3941. Rubin CM, Larson RA, Anastasi J, Winter JN, Thangavelu M, Vardiman JW, Rowley JD, Le Beau MM. t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood 1990; 76: 2594–2598. Berger R, Bernheim A, Le Coniat M, Veccione D, Pacot A, Daniel M-T, Flandrin G. Abnormalities of the short arm of chromosome 12 in acute nonlymphocytic leukemia and dysmyelopoietic syndrome. Cancer Genet Cytogenet 1986; 19: 281–289. Mimori K, Druck T, Inoue H, Alder H, Berk L, Mori M, Huebner K, Croce CM. Cancer-specific chromosome alterations in the constitutive fragile region FRA3B. Proc Natl Acad Sci USA 1999; 96: 7456–7461. Sutherland GR, Baker E, Richards RI. Fragile sites still breaking. Trends Genet 1998; 14: 501–506. Le Beau MM, Rassool FV, Neilly ME, Espinosa R III, Glover TW, Smith DI, McKeithan TW. Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction. Hum Mol Genet 1998; 7: 755–761. Wang L, Darling J, Zhang JS, Huang H, Liu W, Smith DI. Allelespecific late replication and fragility of the most active common site, FRA3B. Hum Mol Genet 1999; 8: 431–437.