Abstract
The current study was undertaken to search for differences in the biology of cytogenetic subgroups in patients with de novo acute myeloid leukemia (AML). In addition, factors influencing the metabolism of cytosine arabinoside (araC) as the key agent of antileukemic activity were assessed. Bone marrow aspirates from 91 patients with newly diagnosed AML in whom karyotypes were successfully obtained were analyzed: (1) for spontaneous proliferative activity by 3H-thymidine (3H-TdR) incorporation; (2) proliferative response to GM-CSF by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4-h exposure to 3H-TdR (0.5 μCi/ml); and (3) parameters of araC metabolism comprising 3H-araC uptake in vitro and the activities of polymerase alpha (poly α), deoxycytidine kinase (DCK) and deoxycytidine deaminase (DCD). According to the results of chromosome analyses four cytogenetic subgroups were discriminated: (I) normal karyotypes (n = 38); (II) favorable karyotypes [t8;21), t(15;17), inv(16)] (n = 16); (III) unfavorable karyotypes [inv (3), −5, 5q−, t(6;9), +8, t (9;11), complex abnormalities] (n = 20); (IV) karyotypes of unknown prognostic significance (n = 17). Proliferative activity of leukemic blasts was significantly higher in favorable karyotypes (group II) as compared to cases with unfavorable cytogenetics (group III) with median values and range for 3H-TdR uptake in group II of 2.48 pmol/105 cells (0.28–25.8) and in group III of 0.51 pmol/105 cells (0.04–7.6) (P = 0.0096). The respective values in group I and group IV were 0.7 pmol/105 cells (0.0–6.7) and 0.98 pmol/105 cells (0.0–4.0), respectively. Inversely, response to GM-CSF, as defined by an increase in 3H-TdR incorporation >1.5- fold over control values after 48 h of GM-CSF exposure, was significantly lower for patients with a favorable karyotype (group II) as compared to group I (P = 0.04) and group III (P = 0.013). No significant differences between karyotype groups I, II, III and IV were found for 3H-araC incorporation, nor for the activities of poly α, DCK and DCD. These data demonstrate differences in the biology of cytogenetic subgroups in AML which may partly explain the well established differences in clinical outcome.
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
Cassileth PA, Lynch E, Hines JD, Oken MM, Mazza JJ, Bennett JM, McGlave PB, Edelstein M, Harrington DP, O'Connel MJ . Varying intensity of postremission therapy in acute myeloid leukemia Blood 1992 79: 1924–1930
Stone RM, Mayer RJ . Treatment of the newly diagnosed adult with de novo acute myeloid leukemia. In: Bloomfield CD, Herzig GP, Chohan N, Kaiser N (eds) Hematology/Oncology: Clinics of North America: Management of Acute Leukemia WB Saunders: Philadelphia 1993 pp 47–54
Mitus AJ, Miller KB, Schenkein DP, Ryan HF, Parsons SK, Wheeler C, Antin JH . Improved survival for patients with acute myelogenous leukemia J Clin Oncol 1995 13: 560–569
Büchner T . Treatment of adult acute leukemia Curr Opin Oncol 1997 9: 18–25
Arthur DC, Berger R, Golomb HM, Swansbury GJ, Reeves BR, Alimena G, Van Den Berghe H, Bloomfield CD, de la Chapelle A, Dewald GW, Garson OM, Hagemejer A, Kanedo Y, Mitelman F, Pierre RV, Ruutu T, Sakurai M, Lawler SD, Rowley JD . The clinical significance of karyotype in acute myelogenous leukemia Cancer Genet Cytogenet 1989 40: 203–216
Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A . The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial Blood 1998 92: 2322–2333
Dastugue N, Payen C, Lafage-Pochitaloff M, Bernard P, Leroux D, Huguet-Rigal F, Stoppa A-M, Marit G, Molina L, Michallet M, Maraninchi D, Attal M, Reiffers J for the BGMT group . Prognostic significance of karyotype in de novo adult acute myeloid leukemia Leukemia 1995 9: 1491–1498
Marlton P, Keating M, Kantarjian H, Pierce S, O'Brien S, Freireich EJ, Estey E . Cytogenetic and clinical correlates in AML patients with abnormalities of chromosome 16 Leukemia 1995 9: 965–971
Schoch C, Haase D, Haferlach T, Gudat H, Buchner T, Freund M, Link H, Lengfelder E, Wandt H, Sauerland MC, Loeffler H, Fonatsch C . Fifty-one patients with acute myeloid leukemia and translocation t(8;21)(q22;22): an additional deletion in 9q is an adverse prognostic factor Leukemia 1996 10: 1288–1295
Bishop JF . Approaches to induction therapy with adult acute myeloid leukemia Acta Haematol 1998 99: 133–137
Kern W, Aul C, Maschmeyer G, Schonrock-NabulsiR, Ludwig WD, Bartholomaus A, Bettelheim P, Wormann B, Buchner T, Hiddemann W . Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leukemia: results of an age-adjusted prospective randomized comparison Leukemia 1998 12: 1049–1055
Mrozek K, Heinonen K, de la Chapelle A, Bloomfield CD . Clinical significance of cytogenetics in acute myeloid leukemia Semin Oncol 1997 24: 17–31
Büchner T, Hiddemann W, Wörmann B, Zühlsdorf M, Aswald J, Aswald S, Rottmann R, Maschmeier G, Ludwig, W-D, Sauerland M-C, Heinecke A for the AMLCG . Age and karyotype-dependent effect of GM-CSF multiple course priming in AML Blood 1996 88: (Suppl. 1) 214a (Abstr.)
Jahns-Streubel G, Haase D, Schoch C, Wörmann B, Büchner T, Fonatsch C, Hiddemann W . Cytogenetic subgroups of acute myeloid leukemia (AML) differ significantly in proliferative activity, cytokine production and sensitivity to GM-CSF stimulation Blood 1996 88: (Suppl. 1) 560a (Abstr.)
Bloomfield CD, Lawrence D, Byrd JC, Carroll A, Pettenati MJ, Tantravahi R, Patil SR, Davey FR, Berg DT, Schiffer CA, Arthur DC, Mayer RJ . Frequency of prolonged remission duration after high-dose cytarabine intensification varies by cytogenetic subgroup Cancer Res 1998 58: 4173–4179
Büchner T, Hiddemann W, Wörmann B, Löffler H, Gassmann W, Haferlach T, Fonatsch C, Haase D, Schoch C, Hossfeld D, Lengfelder E, Aul C, Heyll A, Maschmeyer G, Ludwig W, Sauerland M, Heinecke A . Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group Blood 1999 93: 4116–4124
Mayer R, Davis R, Schiffer C, Berg D, Powell B, Schulman P, Omura G, Moore J, McIntyre R, Frei E for the Cancer and Leukemia Group B . Intensive postremission chemotherapy in adults with acute myeloid leukemia N Engl J Med 1994 331: 896–903
Bhalla K, Holladay C, Arlin Z, Grant S, Ibrado AM, Jasiok M . Treatment with interleukin-3 plus granulocyte–macrophage colony-stimulating factors improves the selectivity of ara-C in vitro against acute myeloid leukemia blasts Blood 1991 78: 2674–2679
Van der Lely N, De Witte T, Muus P, Raymakers R, Preijers F . Prolonged exposure to cytosine arabinoside in the presence of hematopoietic growth factors preferentially kills leukemic vs normal clonogenic cells Exp Hematol 1991 19: 267–272
Te Boekhorst PAW, Löwenberg B, Vlastuin M, Sonneveldt P . Enhanced chemosensitivity of clonogenic blasts from patients with acute myeloid leukemia by G-CSF, IL-3 and GM-CSF stimulation Leukemia 1993 7: 1191–1198
Tafuri A, Lemoli RM, Chen R, Gulati SC, Clarkson BD, Andreef M . Combination of hematopoietic growth factors containing IL-3 induce acute myeloid leukemia cell sensitization to cycle specific and cycle non-specific drugs Leukemia 1994 8: 749–759
Reuter C, Auf der Landwehr U, Schleyer E, Zuhlsdorf M, Ameling C, Rolf C, Wörmann B, Büchner T, Hiddemann W . Modulation of intracellular metabolism of cytosine arabinoside in acute myeloid leukemia by granulocyte–macrophage colony-stimulating factor Leukemia 1994 8: 217–225
Bettelheim P, Valent P, Andreef M, Tafuri A, Haimi J, Gorischek C, Muhm M, Sillaber C, Haas O, Vieder L . Recombinant human granulocyte–macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia Blood 1991 77: 700–711
Estey E, Thall PF, Kantarjian H, O'Brien S, Coller CA, Beran M, Guttermann J, Deisseroth A, Keating M . Treatment of newly diagnosed acute myelogenous leukemia with granulocyte-macrophage colony-stimulating factor (GM-CSF) before and during continous-infusion high-dose araC + daunorubicin: comparison to patients treated without GM-CSF Blood 1992 79: 2246–2255
Büchner T, Hiddemann W, Wörmann B, Rottmann R, Zühlsdorf M, Maschmeyer G, Ludwig WO, Sauerland MC, Frisch J, Schulz G . Hematopoietic growth factors in acute myeloid leukemia Semin Oncol 1997 24: 124–131
Schiffer CA . Hematopoietic growth factors as adjuncts to the treatment of acute myeloid leukemia Blood 1996 88: 3675–3685
Zittoun R, Suciu S, Mandelli F, de Witte T, Thaler J, Stryckmans P, Hayat M, Peetermans M, Cadiou M, Solbu G . Granulocyte–macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: a randomized trial by the European Organization for Research J Clin Oncol 1996 14: 2150–2159
Rowe JM, Liesveld JL . Hematopoietic growth factors in acute leukemia Leukemia 1997 11: 328–341
Löwenberg B, Suciu S, Archimbaud E, Ossenkoppele G, Verhoef GE, Vellenga E, Wijermans P, Berneman Z, Dekker AW, Stryckmans P, Schouten H, Jehn U, Muus P, Sonneveld P, Dardenne M, Zittoun R . Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group Blood 1997 90: 2952–2961
Witz F, Sadoun A, Perrin MC, Berthou C, Briere J, Cahn JY, Lioure B, Witz B, Francois S, Desablens B, Pignon B, Le Prise PY, Audhuy B, Caillot D, Casassus P, Delain M, Christian B, Tellier Z, Polin V, Hurteloup P, Harousseau JL . A placebo-controlled study of recombinant human granulocyte–macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM) Blood 1998 91: 2722–2730
Tattersall MHN, Ganeshaguru K, Hoffbrand AV . Mechanisms of resistance of human acute leukemia cells to cytosine arabinoside Br J Haematol 1974 27: 39–46
Colly LP, Peters WG, Riche D, Arentsen-Honder MW, Starrenburg CW, Willemze R . Deoxycytidine kinase and deoxycytidine deaminase values correspond closely to clinical response to cytosine arabinoside remission induction therapy in patients with acute myelogenous leukemia Semin Oncol 1987 14: 257–261
Liliemark JO, Plunkett W . Regulation of 1-β-D arabinofuranosylcytosine 5′-triphosphate accumulation in human leukemic cells by deoxycytidine 5′ triphosphate Cancer Res 1986 46: 1079–1083
Jamieson GP, Snook MB, Wiley JS . Saturation of intracellular cytosine arabinoside triphosphate accumulation in human leukemic blasts Leukemia Res 1990 14: 475–479
Jahns-Streubel G, Reuter C, Auf der Landwehr U, Unterhalt M, Schleyer E, Wörmann B, Büchner T, Hiddemann W . Activity of thymidine kinase, polymerase α, as well as activity and gene expression of deoxycytidine deaminase in leukemic blasts are correlated with clinical response in the setting of GM-CSF based priming before and during TAD-9 induction therapy in acute myeloid leukemia Blood 1997 90: 1968–1976
Stuart DC, Burke P . Cytidine deaminase and development of resistance to arabinosylcytosine Nature New Biol 1971 233: 109–110
Smyth JF, Robins AB, Leese CL . The metabolism of cytosine arabinoside as a predictive test for clinical response to the drug in acute myeloid leukemia Eur J Cancer 1976 12: 567–573
Chiba T, Tihan T, Szekeres T, Salamon J, Kraupp M, Eher R, Köller U, Knapp W . Concordant changes in pyrimidine metabolism in blasts of two cases of acute myeloid leukemia after repeated treatment with ara-C in vivo Leukemia 1990 4: 761–765
Hillen H, Wessels J, Haanen C . Bone marrow proliferation patterns in acute myeloblastic leukemia determined by pulse cytophotometry Lancet 1975 15: 609–611
Kantarjian HM, Barlogie B, Keating MJ, Hal RR . Pretreatment cytokinetics in acute myeloid leukemia J Clin Invest 1985 76: 319–324
Raza A, Preisler HD, Day R, Yasin Z, White M, Lykins J, Kukla C, Barcos M, Bennett J, Browman G, Goldberg J, Grunwald H, Larson R, Vardiman J, Vogler R . Direct relationship between remission duration in acute myeloid leukemia and cell cycle kinetics: a Leukemia Intergroup Study Blood 1990 76: 2191–2197
Löwenberg B, Van Putten WLJ, Touw IP, Delwel R, Santini V . Autonomous proliferation of leukemic cells as a determinant of prognosis in adult acute myeloid leukemia N Engl J Med 1993 328: 614–619
Jahns-Streubel G, Reuter C, Unterhalt M, Schleyer E, Wörmann B, Büchner T, Hiddemann W . Blast cell proliferative activity and sensitivity to GM-CSF in vitro are associated with early response to TAD-9 induction therapy in acute myeloid leukemia Leukemia 1995 9: 1857–1863
Cozzolino F, Rubartelli A, Aldinucci D, Sita R, Torcia M, Shaw A, Di Guglielmo R . Interleukin 1 as an autocrine growth factor for acute myeloid leukemia cells Proc Natl Acad Sci USA 1989 86: 2369–2373
Oster W, Nicola AC, Klein H, Hirano T, Kishimoto T, Lindemann A, Mertelsmann RH, Hermann F . Participation of the cytokines interleukin-6, tumor necrosis factor-alpha and interleukin 1-beta secreted by acute myelogenous leukemia blasts in autocrine and paracrine growth control J Clin Invest 1989 84: 451–457
Murohashi I, Tohda S, Imai Y, Hirai Y, Nara N . Growth potentiating activity of endogenous production of interleukin-1 and tumor necrosis factor α in blast cells of acute myeloblastic leukemia Exp Hematol 1993 21: 846–851
Bradbury D, Rogers S, Reilly IAG, Kozlowski R, Russell NH . Role of autocrine and paracrine production of granulocyte–macrophage colony-stimulating factor and interleukin-1β in the autonomous growth of acute myeloblastic leukemia cells – studies using purified CD34–positive cells Leukemia 1992 6: 562–566
Tsuzuki M, Ezaki K, Maruyama F, Ino T, Kojima H, Okamoto M, Yamaguchi T, Nomura T, Miyazaki H, Wakita M, Matsui T, Hirano M . Proliferative effects of several hematopoietic growth factors on acute myelogenous leukemia cells an correlation with treatment outcome Leukemia 1997 11: 2125–2130
Whitehead VM, Vuchich MJ, Lauer SJ, Mahoney D, Carroll AJ, Shuster JJ, Esseltine DW, Payment C, Look AT, Akabutu J, Bowen T, Taylor LD, Camitta B, Pullen DJ . Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (<50 chromosomes) B-lineage acute lymphoblastic leukemia: A Pediatric Oncology Group Study Blood 1992 80: 1316–1323
Whitehead VM, Vuchich MJ, Cooley L, Lauer SJ, Mahoney DH, Shuster JJ, Payment C, Bernstein ML, Akabutu JJ, Bowen T, Kamen BA, Watson MS, Look AT, Pullen DJ, Camitta B . Translocations involving chromosome 12p11–13, methotrexate metabolism, and childhood B-progenitor cell acute lymphoblastic leukemia: a Pediatric Oncology Group study Clin Cancer Res 1988 4: 183–188
Büchner T, Urbanitz D, Hiddemann W, Rühl H, Ludwig WD, Fischer J, Aul HC, Vaupel HA, Kuse R, Zeile G, Nowrousian MR, König HJ, Walter M, Wendt FC, Sodomann H, Hossfeld DK, von Paleske A, Löffler H, Gassmann W, Hellriegel K-P, Fülle HH, Lunschken C, Emmerich B, Pralle H, Pees HW, Pfreundschuh M, Bartels H, Koeppen K-M, Schwerdtfeger R, Donhuijsen-Ant R, Mainzer K, Bonfert A . Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group J Clin Oncol 1985 3: 1583–1589
Büchner T, Hiddemann W, Löffler G, Gassmann W, Maschmeyer G, Heit W, Hossfeld D, Weh H, Ludwig W-D, Thiel E, Nowrousian M, Aul C, Lengfelder E, Lathan B, Mainzer K, Urbanitz D, Emmerich B, Middelhoff G, Donhuijsen-Ant HR, Hellriegel H-P, Heinecke A . Improved cure rate by early intensification combined with prolonged maintenance chemotherapy in patients with acute myeloid leukemia: data from the AML Cooperative Group Semin Hematol 1991 28: 76–79
Fonatsch C, Schaadt M, Kirchner H, Diehl V . A possible correlation between the degree of karyotype aberrations and the rate of sister chromatid exchanges in lymphoma cell lines Int J Cancer 1980 26: 749–750
Stollmann B, Fonatsch C, Havers W . Persistent Epstein–Barr virus infection associated with monosomy 7 or chromosome 3 abnormality in childhood myeloproliferative disorders Br J Haematol 1985 60: 183–196
Mitelman F (ed) . ISCN: An International System for Human Cytogenetic Nomenclature S Karger: Basel 1995
Sambrook J, Fritsch EF, Maniatis T . Molecular Cloning A Laboratory Manual vol III, second edn: Cold Spring Harbor Laboratory Press: Cold Spring Harbor 1989 E19
Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ . Protein measurement with the folin phenol reagent J Biol Chem 1951 193: 265–272
Tanaka S, Hu SZ, Shu-Fong Wang T, Korn D . Preparation and preliminary characterization of monoclonal antibodies against human polymerase J Biol Chem 1962 257: 519–525
Aposhian HV, Kornberg A . Enzymatic synthesis of deoxyribonucleic acid J Biol Chem 1962 237: 519–525
Hammond RA, Byrnes JJ, Miller MR . Identification of DNA polymerases in CV-1 cells: studies implicating both DNA polymerase alpha and DNA polymerase delta in DNA replication Biochemistry 1987 26: 6817–6824
Saunders PP, Lai MM . Nucleoside kinase activities of Chinese hamster ovary cells Biochem Biophys Acta 1983 761: 135–141
Banker DE, Groudine M, Norwood T, Appelbaum FR . Measurement of spontaneous and therapeutic agent-induced apoptosis with bcl-2 protein expression in acute myeloid leukemia Blood 1997 89: 243–255
Tien HF, Wang CH, Chuang SM, Lee FY, Liu MC, Chen YC, Shen MC, Lin DT, Lin KH, Lin KS, Liu CH . Characterization of Philadelphia-chromosome-positive acute leukemia by clinical, immunocytochemical and gene analysis Leukemia 1992 6: 907–914
Prokocimer M, Rotter V . Structure and function of p53 in normal cells and their aberrations in cancer cells: projection on the hematologic cell lineages Blood 1994 84: 2391–2411
Smith DB, Bambach BJ, Vala MS, Barber JP, Enger C, Brodsky RA, Burke PJ, Gore SD, Jones RJ . Inhibited apoptosis and drug resistance in acute myeloid leukemia Br J Haematol 1998 102: 1042–1049
Askew DS, Ashmun RA, Simmons BC, Cleveland JL . Constitutive c-myc expression in an IL-3-dependent myeloid cell line supresses cell cycle arrest and accelerates apoptosis Oncogene 1991 6: 1915–1922
Chelliah J, Freemerman AJ, Wu-Pong S, Jarvis WD, Grant S . Potentiation of ara-C induced apoptosis by the protein kinase C activator bryostatin 1 in human leukemia cells (HL-60) involves a process dependent upon c-myc Biochem Pharmacol 1997 54: 563–573
Hiddemann W, Fonatsch C, Wörmann B, Heinecke A, Sauerland C, Scharnhorst S, Büchner T for the German AML Cooperative Group . Cytogenetic subgroups of AML and outcome from high-dose vs conventional-dose ara-C as part of double induction therapy Blood 1995 86: (Suppl. 1) 267a (Abstr.)
Kita K, Shirakawa S, Kamada N . Cellular characteristics of acute myeloblastic leukemia associated with t(8;21)(q22;q22). The Japanese Cooperative Group of Leukemia/Lymphoma Leuk Lymphoma 1994 13: 229–234
Cremer E, Schoch C, Haase D, Wörmann B, Hiddemann W . G-CSF increases the number of trisomy 8 metaphases in vitro in patients with acute myeloid leukemia or myelodysplastic syndrome Ann Hematol 1997 74: (Suppl. 1) 107 (Abstr.)
Acknowledgements
This study was supported by a grant from the Dr Mildered-Scheel Stiftung für Krebsforschung, Germany (W 131/94/Hi7).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Jahns-Streubel, G., Braess, J., Schoch, C. et al. Cytogenetic subgroups in acute myeloid leukemia differ in proliferative activity and response to GM-CSF. Leukemia 15, 377–384 (2001). https://doi.org/10.1038/sj.leu.2402029
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2402029
Keywords
This article is cited by
-
Acute myeloid leukemia with t(19;21)(q13;q22) and marked eosinophilia
Annals of Hematology (2019)
-
Restoration of MYC-repressed targets mediates the negative effects of GM-CSF on RUNX1-ETO leukemogenicity
Leukemia (2017)
-
Timed-sequential chemotherapy with concomitant granulocyte colony-stimulating factor for newly diagnosed de novo acute myelogenous leukemia
Leukemia (2003)