Clinical implications of molecular genetic aberrations in acute myeloid leukemia

  • Sebastian Scholl
  • Hans-Joerg Fricke
  • Herbert G. Sayer
  • Klaus Höffken
Review

Abstract

The role of different cytogenetic changes has been extensively evaluated in patients with acute myeloid leukemia (AML), and cytogenetic analysis of AML blasts is essential to form prognostic subgroups in order to stratify for the extent of therapy. Nevertheless, 40–45% of AML patients lack such cytogenetic markers, i.e., cytogenetically normal AML (CN-AML). In the past decade, different molecular aberrations were identified in AML and especially CN-AML can now be discriminated into certain prognostic subgroups. This review considers the latest advances to define the prognostic impact of molecular aberrations in AML and gives insights how such molecular markers can be applied for analysis of minimal residual disease. Furthermore, therapeutic implications as well as the potential role of new methodological techniques in analyzing expression patterns of AML blasts are discussed.

Keywords

AML MRD Mutations Prognosis 

Abbreviations

CN-AML

Cytogenetically normal acute myeloid leukemia

CIR

Cumulative incidence of relapse

CR

Complete remission

DFS

Disease free survival

EFS

Event free survival

GEP

Gene expression profiling

MRD

Minimal residual disease

OS

Overall survival

References

  1. Andersson A, Johansson B, Lassen C, Mitelman F, Billström R, Fioretos T (2004) Clinical impact of internal tandem duplications and activating point mutations in FLT3 in acute myeloid leukemia in elderly patients. Eur J Haematol 72:307–313. doi:10.1111/j.1600-0609.2004.00225.x PubMedCrossRefGoogle Scholar
  2. Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S (2006) Implications of NRAS mutations in AML: a study of 2,502 patients. Blood 107:3847–3853. doi:10.1182/blood-2005-08-3522 PubMedCrossRefGoogle Scholar
  3. Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S (2008) Prognostic relevance of FLT3-TKD mutations in AML: the combination matters—an analysis of 3082 patients. Blood 111:2527–2537. doi:10.1182/blood-2007-05-091215 PubMedCrossRefGoogle Scholar
  4. 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 (2003) BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood 102:1613–1618. doi:10.1182/blood-2003-02-0359 PubMedCrossRefGoogle Scholar
  5. Baldus CD, Thiede C, Soucek S, Bloomfield CD, Thiel E, Ehninger G (2006) BAALC expression and FLT3 internal tandem duplication mutations in acute myeloid leukemia patients with normal cytogenetics: prognostic implications. J Clin Oncol 24:790–797. doi:10.1200/JCO.2005.01.6253 PubMedCrossRefGoogle Scholar
  6. Balkhi MY, Trivedi AK, Geletu M, Christopeit M, Bohlander SK, Behre HM, Behre G (2006) Proteomics of acute myeloid leukaemia: cytogenetic risk groups differ specifically in their proteome, interactome and post-translational protein modifications. Oncogene 25:7041–7058. doi:10.1038/sj.onc.1209689 PubMedCrossRefGoogle Scholar
  7. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, Meijer J, van Oosterhoud S, van Putten WL, Valk PJ, Berna Beverloo H, Tenen DG, Löwenberg B, Delwel R (2003a) Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. Hematol J 4:31–40. doi:10.1038/sj.thj.6200216
  8. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel-van de Luytgaarde S, Hack R, Slater R, Smit EM, Beverloo HB, Verhoef G, Verdonck LF, Ossenkoppele GJ, Sonneveld P, de Greef GE, Löwenberg B, Delwel R (2003b) High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood 101:837–845. doi:10.1182/blood-2002-05-1459
  9. Bienz M, Ludwig M, Leibundgut EO, Mueller BU, Ratschiller D, Solenthaler M, Fey MF, Pabst T (2005) Risk assessment in patients with acute myeloid leukemia and a normal karyotype. Clin Cancer Res 11:1416–1424. doi:10.1158/1078-0432.CCR-04-1552 PubMedCrossRefGoogle Scholar
  10. Boissel N, Leroy H, Brethon B, Philippe N, de Botton S, Auvrignon A, Raffoux E, Leblanc T, Thomas X, Hermine O, Quesnel B, Baruchel A, Leverger G, Dombret H, Preudhomme C (2006) Acute Leukemia French Association (ALFA); Leucémies Aiguës Myéloblastiques de l’Enfant (LAME) Cooperative Groups: incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia 20:965–970. doi:10.1038/sj.leu.2404188 PubMedCrossRefGoogle Scholar
  11. Bornhäuser M, Illmer T, Schaich M, Soucek S, Ehninger G, Thiede C (2007) AML SHG 96 study group: improved outcome after stemcell transplantation in FLT3/ITD positive AML. Blood 109:2264–2265. doi:10.1182/blood-2006-09-047225 PubMedCrossRefGoogle Scholar
  12. Bowen DT, Frew ME, Hills R, Gale RE, Wheatley K, Groves MJ, Langabeer SE, Kottaridis PD, Moorman AV, Burnett AK, Linch DC (2005) RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood 106:2113–2119. doi:10.1182/blood-2005-03-0867 PubMedCrossRefGoogle Scholar
  13. Bullinger L, Döhner K, Bair E, Fröhling S, Schlenk RF, Tibshirani R, Döhner H, Pollack JR (2004) Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 350:1605–1616. doi:10.1056/NEJMoa031046 PubMedCrossRefGoogle Scholar
  14. Bullinger L, Rücker FG, Kurz S, Du J, Scholl C, Sander S, Corbacioglu A, Lottaz C, Krauter J, Fröhling S, Ganser A, Schlenk RF, Döhner K, Pollack JR, Döhner H (2007) Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia. Blood 110:1291–1300. doi:10.1182/blood-2006-10-049783 PubMedCrossRefGoogle Scholar
  15. Bullinger L, Döhner K, Kranz R, Stirner C, Fröhling S, Scholl C, Kim YH, Schlenk RF, Tibshirani R, Döhner H, Pollack JR (2008) An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML. Blood 111:4490–4495. doi:10.1182/blood-2007-09-115055 PubMedCrossRefGoogle Scholar
  16. Buonamici S, Ottaviani E, Testoni N, Montefusco V, Visani G, Bonifazi F, Amabile M, Terragna C, Ruggeri D, Piccaluga PP, Isidori A, Malagola M, Baccarani M, Tura S, Martinelli G (2002) Real-time quantitation of minimal residual disease in inv(16)-positive acute myeloid leukemia may indicate risk for clinical relapse and may identify patients in a curable state. Blood 99:443–449. doi:10.1182/blood.V99.2.443 PubMedCrossRefGoogle Scholar
  17. Burnett AK, Kell J (2007) Tipifarnib in acute myeloid leukemia. Drugs Today (Barc) 43:795–800CrossRefGoogle Scholar
  18. Cairoli R, Beghini A, Grillo G, Nadali G, Elice F, Ripamonti CB, Colapietro P, Nichelatti M, Pezzetti L, Lunghi M, Cuneo A, Viola A, Ferrara F, Lazzarino M, Rodeghiero F, Pizzolo G, Larizza L, Morra E (2006) Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood 107:3463–3468. doi:10.1182/blood-2005-09-3640 PubMedCrossRefGoogle Scholar
  19. Caligiuri MA, Schichman SA, Strout MP, Mrózek K, Baer MR, Frankel SR, Barcos M, Herzig GP, Croce CM, Bloomfield CD (1994) Molecular rearrangement of the ALL-1 gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocations. Cancer Res 54:370–373PubMedGoogle Scholar
  20. Callens C, Chevret S, Cayuela JM, Cassinat B, Raffoux E, de Botton S, Thomas X, Guerci A, Fegueux N, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Ferrand A, Sanz M, Chomienne C, Fenaux P, Dombret H (2005) European APL Group: prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia 19:1153–1160. doi:10.1038/sj.leu.2403790 PubMedCrossRefGoogle Scholar
  21. Cassinat B, Zassadowski F, Balitrand N, Barbey C, Rain JD, Fenaux P, Degos L, Vidaud M, Chomienne C (2000) Quantitation of minimal residual disease in acute promyelocytic leukemia patients with t(15;17) translocation using real-time RT-PCR. Leukemia 14:324–328. doi:10.1038/sj.leu.2401652 PubMedCrossRefGoogle Scholar
  22. Cazzaniga G, Dell’Oro MG, Mecucci C, Giarin E, Masetti R, Rossi V, Locatelli F, Martelli MF, Basso G, Pession A, Biondi A, Falini B (2005) Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Blood 106:1419–1422. doi:10.1182/blood-2005-03-0899 PubMedCrossRefGoogle Scholar
  23. Chou WC, Tang JL, Wu SJ, Tsay W, Yao M, Huang SY, Huang KC, Chen CY, Huang CF, Tien HF (2007) Clinical implications of minimal residual disease monitoring by quantitative polymerase chain reaction in acute myeloid leukemia patients bearing nucleophosmin (NPM1) mutations. Leukemia 21:998–1004PubMedGoogle Scholar
  24. Choudhary C, Schwäble J, Brandts C, Tickenbrock L, Sargin B, Kindler T, Fischer T, Berdel WE, Müller-Tidow C, Serve H (2005) AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations. Blood 106:265–273. doi:10.1182/blood-2004-07-2942 PubMedCrossRefGoogle Scholar
  25. Cui JW, Wang J, He K, Jin BF, Wang HX, Li W (2004) Proteomic analysis of human acute leukemia cells: insight into their classification. Clin Cancer Res 10:6887–6896. doi:10.1158/1078-0432.CCR-04-0307 PubMedCrossRefGoogle Scholar
  26. Döhner K, Tobis K, Ulrich R, Fröhling S, Benner A, Schlenk RF, Döhner H (2002) Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16–60 years old with acute myeloid leukemia and normal cytogenetics: a study of the Acute Myeloid Leukemia Study Group Ulm. J Clin Oncol 20:3254–3261. doi:10.1200/JCO.2002.09.088 PubMedCrossRefGoogle Scholar
  27. Döhner K, Schlenk RF, Habdank M, Scholl C, Rücker FG, Corbacioglu A, Bullinger L, Fröhling S, Döhner H (2005) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106:3740–3746. doi:10.1182/blood-2005-05-2164 PubMedCrossRefGoogle Scholar
  28. 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 (2005) GIMEMA Acute Leukemia Working Party: cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352:254–266. doi:10.1056/NEJMoa041974 PubMedCrossRefGoogle Scholar
  29. Fröhling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, Döhner H, Döhner K (2002) AML Study Group Ulm: acute myeloid leukemia. Prognostic significance of activating FLT3 mutations in younger adults (16–60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 100:4372–4380. doi:10.1182/blood-2002-05-1440 PubMedCrossRefGoogle Scholar
  30. Fröhling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, Tobis K, Döhner H, Döhner K (2004) CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 22:624–633. doi:10.1200/JCO.2004.06.060 PubMedCrossRefGoogle Scholar
  31. Gale RE, Hills R, Pizzey AR, Kottaridis PD, Swirsky D, Gilkes AF, Nugent E, Mills KI, Wheatley K, Solomon E, Burnett AK, Linch DC, Grimwade D (2005a) NCRI Adult Leukaemia Working Party: Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 106:3768–3776. doi:10.1182/blood-2005-04-1746 PubMedCrossRefGoogle Scholar
  32. Gale RE, Hills R, Kottaridis PD, Srirangan S, Wheatley K, Burnett AK, Linch DC (2005b) No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1,135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood 106:3658–3665. doi:10.1182/blood-2005-03-1323 PubMedCrossRefGoogle Scholar
  33. Garzon R, Garofalo M, Martelli MP, Briesewitz R, Wang L, Fernandez-Cymering C, Volinia S, Liu CG, Schnittger S, Haferlach T, Liso A, Diverio D, Mancini M, Meloni G, Foa R, Martelli MF, Mecucci C, Croce CM, Falini B (2008) Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci USA 105:3945–3950. doi:10.1073/pnas.0800135105 PubMedCrossRefGoogle Scholar
  34. Gleixner KV, Mayerhofer M, Aichberger KJ, Derdak S, Sonneck K, Böhm A, Gruze A, Samorapoompichit P, Manley PW, Fabbro D, Pickl WF, Sillaber C, Valent P (2006) PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects. Blood 107:752–759. doi:10.1182/blood-2005-07-3022 PubMedCrossRefGoogle Scholar
  35. Gombart AF, Hofmann WK, Kawano S, Takeuchi S, Krug U, Kwok SH, Larsen RJ, Asou H, Miller CW, Hoelzer D, Koeffler HP (2002) Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood 99:1332–1340. doi:10.1182/blood.V99.4.1332 PubMedCrossRefGoogle Scholar
  36. Gorello P, Cazzaniga G, Alberti F, Dell’Oro MG, Gottardi E, Specchia G, Roti G, Rosati R, Martelli MF, Diverio D, Lo Coco F, Biondi A, Saglio G, Mecucci C, Falini B (2006) Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia 20:1103–1108. doi:10.1038/sj.leu.2404149 PubMedCrossRefGoogle Scholar
  37. Gotlib J (2005) Farnesyltransferase inhibitor therapy in acute myelogenous leukemia. Curr Hematol Rep 4:77–84PubMedGoogle Scholar
  38. Graf C, Heidel F, Tenzer S, Radsak MP, Solem FK, Britten CM, Huber C, Fischer T, Wölfel T (2007) A neoepitope generated by an FLT3 internal tandem duplication (FLT3-ITD) is recognized by leukemia-reactive autologous CD8+ T cells. Blood 109:2985–2988PubMedGoogle Scholar
  39. Grosveld GC (2007) MN1, a novel player in human AML. Blood Cells Mol Dis 39:336–339. doi:10.1016/j.bcmd.2007.06.009 PubMedCrossRefGoogle Scholar
  40. Grundler R, Miething C, Thiede C, Peschel C, Duyster J (2005) FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood 105:4792–4799. doi:10.1182/blood-2004-11-4430 PubMedCrossRefGoogle Scholar
  41. Haas K, Kundi M, Sperr WR, Esterbauer H, Ludwig WD, Ratei R, Koller E, Gruener H, Sauerland C, Fonatsch C, Valent P, Wieser R (2008) Expression and prognostic significance of different mRNA 5′-end variants of the oncogene EVI1 in 266 patients with de novo AML: EVI1 and MDS1/EVI1 overexpression both predict short remission duration. Genes Chromosomes Cancer 47:288–298. doi:10.1002/gcc.20532 PubMedCrossRefGoogle Scholar
  42. Heuser M, Beutel G, Krauter J, Döhner K, von Neuhoff N, Schlegelberger B, Ganser A (2006) High meningeoma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood 108:3898–3905. doi:10.1182/blood-2006-04-014845 PubMedCrossRefGoogle Scholar
  43. Hutchings Y, Osada T, Woo CY, Clay TM, Lyerly HK, Morse MA (2007) Imunotherapeutic targeting of Wilms’ tumor protein. Curr Opin Mol Ther 9:62–69PubMedGoogle Scholar
  44. Jiang Y, Dunbar A, Gondek LP, Mohan S, Rataul M, O’Keefe C, Saunthararajah Y, Maciejewski JP (2008) Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood 2008(Oct):2. Epub ahead of printGoogle Scholar
  45. Jongen-Lavrencic M, Sun SM, Dijkstra MK, Valk PJ, Löwenberg B (2008) MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood 111:5078–5085. doi:10.1182/blood-2008-01-133355 PubMedCrossRefGoogle Scholar
  46. King-Underwood L, Pritchard-Jones K (1998) Wilms’ tumor (WT1) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance. Blood 91:2961–2968PubMedGoogle Scholar
  47. Kornblau SM, Tibes R, Qiu Y, Chen W, Kantarjian HM, Andreeff M, Coombes KR, Mills GB (2008) Functional proteomic profiling of AML predicts response and survival. Blood 2008(Oct):7. Epub ahead of printGoogle Scholar
  48. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, Walker H, Wheatley K, Bowen DT, Burnett AK, Goldstone AH, Linch DC (2001) The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98:1752–1759. doi:10.1182/blood.V98.6.1752 PubMedCrossRefGoogle Scholar
  49. Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT, Linch DC (2002) Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood 100:2393–2398. doi:10.1182/blood-2002-02-0420 PubMedCrossRefGoogle Scholar
  50. Krauter J, Hoellge W, Wattjes MP, Nagel S, Heidenreich O, Bunjes D, Ganser A, Heil G (2001) Detection and quantification of CBFB/MYH11 fusion transcripts in patiens with inv(16)-positive acute myeloblastic leukemia by real-time RT-PCR. Genes Chromosomes Cancer 30:342–348. doi:10.1002/gcc.1100 PubMedCrossRefGoogle Scholar
  51. Krauter J, Gorlich K, Ottmann O, Lubbert M, Dohner H, Heit W, Kanz L, Ganser A, Heil G (2003) Prognostic value of minimal residual disease quantification by real-time reverse transcriptase polymerase chain reaction in patients with core binding factor leukemias. J Clin Oncol 21:4413–4422. doi:10.1200/JCO.2003.03.166 PubMedCrossRefGoogle Scholar
  52. Kroeger H, Jelinek J, Estécio MR, He R, Kondo K, Chung W, Zhang L, Shen L, Kantarjian HM, Bueso-Ramos CE, Issa JP (2008) Aberrant CpG island methylation in acute myeloid leukemia is accentuated at relapse. Blood 112:1366–1373. doi:10.1182/blood-2007-11-126227 PubMedCrossRefGoogle Scholar
  53. Kuchenbauer F, Schoch C, Kern W, Hiddemann W, Haferlach T, Schnittger S (2005) Impact of FLT3 mutations and promyelocytic leukaemia-breakpoint on clinical characteristics and prognosis in acute promyelocytic leukaemia. Br J Haematol 130:196–202. doi:10.1111/j.1365-2141.2005.05595.x PubMedCrossRefGoogle Scholar
  54. Langer C, Radmacher MD, Ruppert AS, Whitman SP, Paschka P, Mrózek K, Baldus CD, Vukosavljevic T, Liu CG, Ross ME, Powell BL, de la Chapelle A, Kolitz JE, Larson RA, Marcucci G, Bloomfield CD (2008) Cancer and Leukemia Group B (CALGB): high BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) Study. Blood 111:5371–5379. doi:10.1182/blood-2007-11-124958 PubMedCrossRefGoogle Scholar
  55. Li Z, Lu J, Sun M, Mi S, Zhang H, Luo RT, Chen P, Wang Y, Yan M, Qian Z, Neilly MB, Jin J, Zhang Y, Bohlander SK, Zhang DE, Larson RA, Le Beau MM, Thirman MJ, Golub TR, Rowley JD, Chen J (2008) Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci USA 105:15535–15540. doi:10.1073/pnas.0808266105 PubMedCrossRefGoogle Scholar
  56. Lugthart S, van Drunen E, van Norden Y, van Hoven A, Erpelinck CA, Valk PJ, Beverloo HB, Löwenberg B, Delwel R (2008) High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood 111:4329–4337. doi:10.1182/blood-2007-10-119230 PubMedCrossRefGoogle Scholar
  57. Marcucci G, Livak KJ, Bi W, Strout MP, Bloomfield CD, Caligiuri MA (1998) Detection of minimal residual disease in patients with AML1/ETO-associated acute myeloid leukemia using a novel quantitative reverse transcription polymerase chain reaction assay. Leukemia 12:1482–1489. doi:10.1038/sj.leu.2401128 PubMedCrossRefGoogle Scholar
  58. Marcucci G, Baldus CD, Ruppert AS, Radmacher MD, Mrózek K, Whitman SP, Kolitz JE, Edwards CG, Vardiman JW, Powell BL, Baer MR, Moore JO, Perrotti D, Caligiuri MA, Carroll AJ, Larson RA, de la Chapelle A, Bloomfield CD (2005) Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B Study. J Clin Oncol 23:9234–9242. doi:10.1200/JCO.2005.03.6137 PubMedCrossRefGoogle Scholar
  59. Marcucci G, Maharry K, Whitman SP, Vukosavljevic T, Paschka P, Langer C, Mrózek K, Baldus CD, Carroll AJ, Powell BL, Kolitz JE, Larson RA, Bloomfield CD (2007) High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol 25:3337–3343. doi:10.1200/JCO.2007.10.8720 PubMedCrossRefGoogle Scholar
  60. Marcucci G, Maharry K, Radmacher MD, Mrózek K, Vukosavljevic T, Paschka P, Whitman SP, Langer C, Baldus CD, Liu CG, Ruppert AS, Powell BL, Carroll AJ, Caligiuri MA, Kolitz JE, Larson RA, Bloomfield CD (2008a) Prognostic significance of, and gene and microrna expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B Study. J Clin Oncol 2008(Sep):22. Epub ahead of printGoogle Scholar
  61. Marcucci G, Radmacher MD, Maharry K, Mrózek K, Ruppert AS, Paschka P, Vukosavljevic T, Whitman SP, Baldus CD, Langer C, Liu CG, Carroll AJ, Powell BL, Garzon R, Croce CM, Kolitz JE, Caligiuri MA, Larson RA, Bloomfield CD (2008b) MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med 358:1919–1928. doi:10.1056/NEJMoa074256 PubMedCrossRefGoogle Scholar
  62. Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE (2007) 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 110:1262–1270. doi:10.1182/blood-2006-04-015826 PubMedCrossRefGoogle Scholar
  63. Meyer C, Schneider B, Jakob S, Strehl S, Attarbaschi A, Schnittger S, Schoch C, Jansen MW, van Dongen JJ, den Boer ML, Pieters R, Ennas MG (2006) The MLL recombinome of acute leukemias. Leukemia 20:777–784. doi:10.1038/sj.leu.2404150 PubMedCrossRefGoogle Scholar
  64. Moreno I, Martín G, Bolufer P, Barragán E, Rueda E, Román J, Fernández P, León P, Mena A, Cervera J, Torres A, Sanz MA (2003) Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. Haematologica 88:19–24PubMedGoogle Scholar
  65. Mullighan CG, Kennedy A, Zhou X, Radtke I, Phillips LA, Shurtleff SA, Downing JR (2007) Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias. Leukemia 21:2000–2009. doi:10.1038/sj.leu.2404808 PubMedCrossRefGoogle Scholar
  66. Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S (1996) Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 10:1911–1918PubMedGoogle Scholar
  67. Noguera NI, Breccia M, Divona M, Diverio D, Costa V, De Santis S, Avvisati G, Pinazzi MB, Petti MC, Mandelli F, Lo Coco F (2002) Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 11:2185–2189. doi:10.1038/sj.leu.2402723 CrossRefGoogle Scholar
  68. Paschka P, Marcucci G, Ruppert AS, Mrózek K, Chen H, Kittles RA, Vukosavljevic T, Perrotti D, Vardiman JW, Carroll AJ, Kolitz JE, Larson RA, Bloomfield CD (2006) Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol 24:3904–3911. doi:10.1200/JCO.2006.06.9500 PubMedCrossRefGoogle Scholar
  69. Paschka P, Marcucci G, Ruppert AS, Whitman SP, Mrózek K, Maharry K, Langer C, Baldus CD, Zhao W, Powell BL, Baer MR, Carroll AJ, Caligiuri MA, Kolitz JE, Larson RA, Bloomfield CD (2008) Wilms’ tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 26:4595–4602. doi:10.1200/JCO.2007.15.2058 PubMedCrossRefGoogle Scholar
  70. Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de Botton S, Thomas X, Raffoux E, Lamandin C, Castaigne S, Fenaux P, Dombret H (2002) ALFA Group: favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 100:2717–2723. doi:10.1182/blood-2002-03-0990 PubMedCrossRefGoogle Scholar
  71. Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H (2008) German–Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358:1909–1918. doi:10.1056/NEJMoa074306 PubMedCrossRefGoogle Scholar
  72. Schnittger S, Wörmann B, Hiddemann W, Griesinger F (1998) Partial tandem duplications of the MLL gene are detectable in peripheral blood and bone marrow of nearly all healthy donors. Blood 92:1728–1734PubMedGoogle Scholar
  73. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C, Löffler H, Sauerland CM, Serve H, Büchner T, Haferlach T, Hiddemann W (2002) Analysis of FLT3 length mutations in 1,003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 100:59–66. doi:10.1182/blood.V100.1.59 PubMedCrossRefGoogle Scholar
  74. Schnittger S, Schoch C, Kern W, Hiddemann W, Haferlach T (2004) FLT3 length mutations as marker for follow-up studies in acute myeloid leukemia. Acta Haematol 112:68–78. doi:10.1159/000077561 PubMedCrossRefGoogle Scholar
  75. Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF, Haferlach T, Hiddemann W, Falini B (2005) Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 106:3733–3739. doi:10.1182/blood-2005-06-2248 PubMedCrossRefGoogle Scholar
  76. Schnittger S, Kohl TM, Haferlach T, Kern W, Hiddemann W, Spiekermann K, Schoch C (2006) KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 107:1791–1799. doi:10.1182/blood-2005-04-1466 PubMedCrossRefGoogle Scholar
  77. Schoch C, Kohlmann A, Schnittger S, Brors B, Dugas M, Mergenthaler S, Kern W, Hiddemann W, Eils R, Haferlach T (2002) Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles. Proc Natl Acad Sci USA 99:10008–10013. doi:10.1073/pnas.142103599 PubMedCrossRefGoogle Scholar
  78. Scholl S, Loncarevic IF, Krause C, Kunert C, Clement JH, Höffken K (2005) Minimal residual disease based on patient specific Flt3-ITD and -ITT mutations in acute myeloid leukemia. Leuk Res 29:849–853. doi:10.1016/j.leukres.2004.12.001 PubMedCrossRefGoogle Scholar
  79. Scholl S, Mügge LO, Landt O, Loncarevic IF, Kunert C, Clement JH, Höffken K (2007) Rapid screening and sensitive detection of NPM1 (nucleophosmin) exon 12 mutations in acute myeloid leukaemia. Leuk Res 31:1213–1219. doi:10.1016/j.leukres.2006.12.011 CrossRefGoogle Scholar
  80. Shah NP, Lee FY, Luo R, Jiang Y, Donker M, Akin C (2006) Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood 108:286–291. doi:10.1182/blood-2005-10-3969 PubMedCrossRefGoogle Scholar
  81. Shih LY, Huang CF, Wu JH, Lin TL, Dunn P, Wang PN, Kuo MC, Lai CL, Hsu HC (2002) Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood 100:2387–2392. doi:10.1182/blood-2002-01-0195 PubMedCrossRefGoogle Scholar
  82. Shih LY, Huang CF, Wu JH, Wang PN, Lin TL, Dunn P, Chou MC, Kuo MC, Tang CC (2004) Heterogeneous patterns of Flt3 Asp835 mutations in relapsed de novo acute myeloid leukemia: a comparative analysis of 120 paired diagnostic and relapse bone marrow samples. Clin Cancer Res 10:1326–1332. doi:10.1158/1078-0432.CCR-0835-03 PubMedCrossRefGoogle Scholar
  83. Steudel C, Wermke M, Schaich M, Schäkel U, Illmer T, Ehninger G, Thiede C (2003) Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia. Genes Chromosomes Cancer 37:237–251. doi:10.1002/gcc.10219 PubMedCrossRefGoogle Scholar
  84. Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL, Radich JP (2001) FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 97:3589–3595. doi:10.1182/blood.V97.11.3589 PubMedCrossRefGoogle Scholar
  85. Summers K, Stevens J, Kakkas I, Smith M, Smith LL, Macdougall F, Cavenagh J, Bonnet D, Young BD, Lister TA, Fitzgibbon J (2001) Wilms’ tumor 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia 21:550–551. doi:10.1038/sj.leu.2404514 CrossRefGoogle Scholar
  86. Suzuki T, Kiyoi H, Ozeki K, Tomita A, Yamaji S, Suzuki R (2005) Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood 106:2854–2861. doi:10.1182/blood-2005-04-1733 PubMedCrossRefGoogle Scholar
  87. Tanner SM, Austin JL, Leone G, Rush LJ, Plass C, Heinonen K, Mrózek K, Sill H, Knuutila S, Kolitz JE, Archer KJ, Caligiuri MA, Bloomfield CD, de La Chapelle A (2001) BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. Proc Natl Acad Sci USA 98:13901–13906. doi:10.1073/pnas.241525498 PubMedCrossRefGoogle Scholar
  88. Thiede C, Steudel C, Mohr B, Schaich M, Schäkel U, Platzbecker U, Wermke M, Bornhäuser M, Ritter M, Neubauer A, Ehninger G, Illmer T (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99:4326–4335. doi:10.1182/blood.V99.12.4326 PubMedCrossRefGoogle Scholar
  89. Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M, Ehninger G (2006) Prevalence and prognostic impact of NPM1 mutations in 1,485 adult patients with acute myeloid leukemia (AML). Blood 107:4011–4020. doi:10.1182/blood-2005-08-3167 PubMedCrossRefGoogle Scholar
  90. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM, Beverloo HB, Moorhouse MJ, van der Spek PJ, Löwenberg B, Delwel R (2004) Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 350:1617–1628. doi:10.1056/NEJMoa040465
  91. Virappane P, Gale R, Hills R, Kakkas I, Summers K, Stevens J, Allen C, Green C, Quentmeier H, Drexler H, Burnett A, Linch D, Bonnet D, Lister TA, Fitzgibbon J (2008) Mutation of the Wilms’ tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: The United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol 2008(Jul):7. Epub ahead of printGoogle Scholar
  92. Weisser M, Kern W, Schoch, Hiddemann W, Haferlach T, Schnittger S (2005) Risk assessment by monitoring expression levels of partial tandem duplications in the MLL gene in acute myeloid leukemia during therapy. Haematologica 90:881–889Google Scholar
  93. Whitman SP, Liu S, Vukosavljevic T, Rush LJ, Yu L, Liu C, Klisovic MI, Maharry K, Guimond M, Strout MP, Becknell B, Dorrance A, Klisovic RB, Plass C, Bloomfield CD, Marcucci G, Caligiuri MA (2005) The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy. Blood 106:345–352. doi:10.1182/blood-2005-01-0204 PubMedCrossRefGoogle Scholar
  94. 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 (2008) 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 111:1552–1559. doi:10.1182/blood-2007-08-107946 PubMedCrossRefGoogle Scholar
  95. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T (2001) Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97:2434–2439. doi:10.1182/blood.V97.8.2434 PubMedCrossRefGoogle Scholar
  96. Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T (2005) Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 19:1345–1349. doi:10.1038/sj.leu.2403838 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Sebastian Scholl
    • 1
  • Hans-Joerg Fricke
    • 1
  • Herbert G. Sayer
    • 1
  • Klaus Höffken
    • 1
  1. 1.Department of Internal Medicine II (Oncology and Hematology) UniversitätsklinikumJenaGermany

Personalised recommendations