Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Devald G . Fourth International Workshop on Chromosomes in Leukemia 1982: abnormalities of chromosome 3 among 24 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, Billström 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, Björkholm M, Christenson I, Engstedt L, Gahrton G, Johansson B, Järnmark M, Killander A, Lindemalm C, Lindquist R, Lockner D, Lönnkvist B, Mellstedt H, Merk K, Palmblad J, Peterson C, Simonsson B, Stalfelt A-M, Sundström C, Wadman B, Wedelin C, Udén A-M, Ahre A, Öberg G, Öst A . Induction and intensive 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
Paul C, Tidefelt U, Gahrton G, Björkholm M, Järnmark M, Killander A, Kimby E, Liliemark E, Liliemark J, Lindeberg A, Lindquist R, Lockner D, Lönnqvist B, Mellstedt H, Merk K, Palmblad J, Peterson C, Simonsson B, Stalfelt A-M, Sundström C, Wadman B, Wedelin C, Udén A-M, Öberg G, Öst A . A randomized comparison of doxorubicin and doxorubicin-DNA in the treatment of acute nonlymphoblastic leukemia Leuk Lymphoma 1991 3: 355–364
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
Caspersson T, Lomakka G, Zech L . The fluorescence patterns of the human metaphase chromosome – distinguishing characters and variability Hereditas 1971 67: 89–102
ISCN . An International System for Human Cytogenetic Nomenclature. Mitelman F (ed) S Karger: Basel 1995
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
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
Öst Å, Lagerlöf B, Sundström C . A study of reproducibility of the diagnostic criteria for acute leukemia Scand J Haematol 1983 31: 257–266
Infante PF, Rinsky RA, Wagoner JK, Young RJ . Leukemia in benzene workers Lancet 1977 2: 76–78
Brandt L, Nilsson PG, Mitelman F . Occupational exposure to petroleum products in men with acute nonlymphocytic leukemia Br Med J 1978 4: 553
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
Smith MT . The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia Environ Health Perspect 1996 104: 1219–1226
Smith MT, Fanning EW . Report on the workshop entitled: ‘Modeling chemically induced leukemia – implications for benzene risk assessment ’ Leukemia Res 1997 21: 361–374
Snyder R, Hedli CC . An overview of benzene metabolism Environ Health Perspect 1996 104: 1165–1171
Oshimura M, Barrett JC . Chemically induced aneuploidy in mammalian cells: mechanisms and biological significance in cancer Environ Mutagen 1986 8: 129–159
Dekaban A . Persisting clone of cells with an abnormal chromosome in a woman previously irradiated J Nucl Med 1965 6: 740–746
Sutherland GR . Fragile sites on human chromosomes: demonstrations of their dependence on the type of tissue culture medium Science 1977 197: 265–266
Sutherland GR . Heritable fragile sites on human chromosomes II. Distribution, phenotypic effects and cytogenetics Am J Hum Genet 1979 31: 136–148
Yunis JJ, Soreng AC . Constitutional fragile sites and cancer Science 1984 226: 1099–1204
Yunis J, Soreng AL, Bove A . Fragile sites are targets of diverse mutagens and carcinogens Oncogene 1987 1: 59–69
Yunis JJ . Fragile sites and predisposition to leukemia and lymphoma Cancer Genet Cytogenet 1984 12: 85–88
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
Johansson B, Billström 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
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
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 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 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 . Allele-specific late replication and fragility of the most active common site, FRA3B Hum Mol Genet 1999 8: 431–437
Acknowledgements
This work was supported by grants from the Swedish Work Environmental Fund, The Swedish Cancer Fund and the Karolinska Institutet's Funds.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lindquist, R., Forsblom, A., Öst, Å. et al. Mutagen exposures and chromosome 3 aberrations in acute myelocytic leukemia. Leukemia 14, 112–118 (2000). https://doi.org/10.1038/sj.leu.2401622
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2401622