Significant progress in the understanding of the genetic basis of acute myeloid leukemia (AML) has been made during the last 30 years. The aim of the present study was to assess whether the detection of recurrent gene rearrangements by fluorescent in situ hybridization (FISH) studies and NPM1 and FLT3 gene mutations by molecular studies added clinically relevant information to the karyotype in 113 AML patients. Thus, FISH and molecular studies were found to add new information in 22 and 55% of the patients, respectively, particularly in cases with normal karyotype (NK) or when a cytogenetic analysis failed. Patients with NK changed their genetic risk group to favorable in 27 and 29% of cases using FISH and molecular biology studies, respectively. Our results demonstrate that molecular biology and FISH studies provide relevant information in AML and should be routinely performed.

1.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC, 2008.
2.
Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Fenaux P, Preudhomme C: Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia 2008;22:915–931.
3.
Schiffer CA: Molecular characterization of AML: a significant advance or just another prognostic factor? Best Pract Res Clin Haematol 2008;21:621–628.
4.
Baldus CD, Mrózek K, Marcuzzi G, Bloomfield CD: Clinical outcome of the novo acute myeloid leukaemia patients with normal cytogenetics is affected by molecular genetic alterations: a concise review. Br J Haematol 2007;137:387–400.
5.
King M, Rowe J: Recent development in acute myelogenous leukaemia therapy. Oncologist 2007;12(suppl 2):14–21.
6.
Frankfurt O, Licht JD, Tallman MS: Molecular characterization of acute myeloid leukemia and its impact on treatment. Curr Opin Oncol 2007;19:635–649.
7.
Smith ML, Hills RK, Grimwade D: Independent prognostic variables in acute myeloid leukaemia. Blood Rev 2011;25:39–51.
8.
Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, Wheatley K, Harrison CJ, Burnett AK, National Cancer Research Institute Adult Leukaemia Working Group: Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5,876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010;116:354–365.
9.
Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD, European LeukemiaNet: Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453–474.
10.
Shaffer LG, Slovak ML, Campbell LJ (eds): ISCN 2009: An International System for Human Cytogenetic Nomenclature. Recommendations of the International Standing Committee on Human Cytogenetic Nomenclature. Basel, Karger, 2009.
11.
Breems DA, Van Putten WL, De Greef GE, Van Zelderen-Bhola SL, Gerssen-Schoorl KB, Mellink CH, Nieuwint A, Jotterand M, Hagemeijer A, Beverloo HB, Löwenberg B: Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 2008;26:4791–4797.
12.
Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N, Barbany G, Cazzaniga G, Cayuela JM, Cavé H, Pane F, Aerts JL, De Micheli D, Thirion X, Pradel V, González M, Viehmann S, Malec M, Saglio G, van Dongen JJ: Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe Against Cancer program. Leukemia 2003;17:2318–2357.
13.
Van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, Gottardi E, Rambaldi A, Dotti G, Griesinger F, Parreira A, Gameiro P, Diáz MG, Malec M, Langerak AW, San Miguel JF, Biondi A: Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia 1999;13:1901–1928.
14.
Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S: Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996;10:1911–1918.
15.
Boissel N, Renneville A, Biggio V, Philippe N, Thomas X, Cayuela JM, Terre C, Tigaud I, Castaigne S, Raffoux E, De Botton S, Fenaux P, Dombret H, Preudhomme C: Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 2005;106:3618–3620.
16.
Heim S, Mitelman F (eds): Cancer Cytogenetics. Chromosomal and Molecular Genetic Aberrations of Tumor Cells, ed 3. New Yersey, Wiley, 2009.
17.
Döhner K, Döhner H: Molecular characterization of acute myeloid leukemia. Haematologica 2008;93:976–982.
18.
Mrózek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD: Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood 2007;109:431–448.
19.
Fröhling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, Döhner H, Döhner K, AML Study Group Ulm: Acute myeloid leukemia. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002;100:4372–4380.
20.
Fröhling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, Tobis K, Döhner H, Döhner K: CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 2004;22:624–633.
21.
Döhner K, Schlenk RF, Habdank M, Scholl C, Rücker FG, Corbacioglu A, Bullinger L, Fröhling S, Döhner H: Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 2005;106:3740–3746.
22.
Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD, Carroll AJ, Mrózek K, Vardiman JW, George SL, Kolitz JE, Larson RA, Bloomfield CD, Caligiuri MA: Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res 2001; 61:7233–7239.
23.
Baldus CD, Tanner SM, Ruppert AS, Whitman SP, Archer KJ, Marcucci G, Caligiuri MA, Carroll AJ, Vardiman JW, Powell BL, Allen SL, Moore JO, Larson RA, Kolitz JE, de la Chapelle A, Bloomfield CD: BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood 2003;102:1613–1618.
24.
Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, La Starza R, Diverio D, Colombo E, Santucci A, Bigerna B, Pacini R, Pucciarini A, Liso A, Vignetti M, Fazi P, Meani N, Pettirossi V, Saglio G, Mandelli F, Lo-Coco F, Pelicci PG, Martelli MF, GIMEMA Acute Leukemia Working Party: Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005;352:254–266, erratum p 740.
25.
Fröhling S, Skelin S, Liebisch C, Scholl C, Schlenk RF, Döhner H, Döhner K, Acute Myeloid Leukemia Study Group Ulm: Comparison of cytogenetic and molecular cytogenetic detection of chromosome abnormalities in 240 consecutive adult patients with acute myeloid leukemia. J Clin Oncol 2002;20:2480–2485.
26.
Fröhling S, Kayser S, Mayer C, Miller S, Wieland C, Skelin S, Schlenk RF, Döhner H, Döhner K, AML Study Group Ulm: Diagnostic value of fluorescence in situ hybridization for the detection of genomic aberrations in older patients with acute myeloid leukemia. Haematologica 2005;90:194–199.
27.
Haferlach T: Molecular genetic pathways as therapeutic targets in acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 2008:400–411.
28.
Kottaridis PD, Gale RE, Linch DC: Flt3 mutations and leukaemia. Br J Haematol 2003;122:523–538.
29.
Slovak ML, Gundacker H, Bloomfield CD, Dewald G, Appelbaum FR, Larson RA, Tallman MS, Bennett JM, Stirewalt DL, Meshinchi S, Willman CL, Ravindranath Y, Alonzo TA, Carroll AJ, Raimondi SC, Heerema NA: A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare ‘poor prognosis’ myeloid malignancies. Leukemia 2006;20:1295–1297.
30.
Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S: Prognostic relevance of FLT3-TKD mutations in AML: the combination matters – an analysis of 3,082 patients. Blood 2008;111:2527–2537.
31.
Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE: FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood 2007;110:1262–1270.
32.
Whitman SP, Ruppert AS, Radmacher MD, Mrózek K, Paschka P, Langer C, Baldus CD, Wen J, Racke F, Powell BL, Kolitz JE, Larson RA, Caligiuri MA, Marcucci G, Bloomfield CD: FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications. Blood 2008;111:1552–1559.
33.
Fröhling S, Skelin S, Liebisch C, Scholl C, Schlenk RF, Döhner H, Döhner K, Acute Myeloid Leukemia Study Group Ulm: Comparison of cytogenetic and molecular cytogenetic detection of chromosome abnormalities in 240 consecutive adult patients with acute myeloid leukemia. J Clin Oncol 2002;20:2480–2485.
34.
Fröhling S, Kayser S, Mayer C, Miller S, Wieland C, Skelin S, Schlenk RF, Döhner H, Döhner K, AML Study Group Ulm: Diagnostic value of fluorescence in situ hybridization for the detection of genomic aberrations in older patients with acute myeloid leukemia. Haematologica 2005;90:194–199.
35.
Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M, Ehninger G: Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 2006;107:4011–4020.
36.
Falini B, Nicoletti I, Martelli MF, Mecucci C: Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood 2007;109:874–885.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.