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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2010, Vol. 4 Issue (4) : 356-362    https://doi.org/10.1007/s11684-010-0220-5
Research articles
Molecular pathogenesis of acute myeloid leukemia: A diverse disease with new perspectives
Felicitas THOL1,Arnold GANSER1, 2,
1.Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover 30625, Germany; 2.2011-02-21 9:44:35;
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Abstract Acute myeloid leukemia (AML) is a very heterogeneous neoplasm of the hematopoietic stem cell. Despite important achievements in the treatment of AML, the long term survival of patients with the disease remains poor. Understanding the pathogenesis of AML better is crucial for finding new treatment approaches. During AML development hematopoietic precursor cells undergo clonal transformation in a multistep process through acquisition of chromosomal rearrangements and/or different gene mutations. Over recent years, novel gene mutations have been found in patients with AML. These mutations can be divided into two important categories, class I mutations that confer a proliferation advantage and class II mutations that inhibit myeloid differentiation. Screening for some of these mutations is now part of the initial diagnostic work-up in newly diagnosed AML patients. Information about the mutation status of specific genes is useful for risk-stratification, minimal residual disease (MRD) monitoring and increasingly also for targeted therapy, especially for patients with cytogenetically normal AML (CN-AML). Besides chromosomal rearrangements and gene mutations, epigenetic regulation of genes – meaning changes in gene expression by mechanisms other than changes in the underlying DNA sequence – also represents an important mechanism of leukemogenesis. This article reviews some of the most common mutations in CN-AML and gives a perspective of the translation of these discoveries from bench to bedside.
Keywords acute myeloid leukemia      mutations      risk stratification      
Issue Date: 05 December 2010
 Cite this article:   
Felicitas THOL,Arnold GANSER,管理员. Molecular pathogenesis of acute myeloid leukemia: A diverse disease with new perspectives[J]. Front. Med., 2010, 4(4): 356-362.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-010-0220-5
https://academic.hep.com.cn/fmd/EN/Y2010/V4/I4/356
Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin, 2002, 52(1): 23–47
PMID: 11814064
Rowley J D, Golomb H M, Dougherty C. 15/17 translocation, a consistent chromosomalchange in acute promyelocytic leukaemia. Lancet, 1977, 1(8010): 549–550
PMID: 65649
Breems D A, Van Putten W L, De Greef G E, Van Zelderen-Bhola S L, Gerssen-Schoorl K B, Mellink C H, Nieuwint A, Jotterand M, Hagemeijer A, Beverloo H B, L?wenberg B. Monosomal karyotype in acute myeloid leukemia: a better indicatorof poor prognosis than a complex karyotype. J Clin Oncol, 2008, 26(29): 4791–4797
PMID: 18695255
Medeiros B C, Othus M, Fang M, Roulston D, Appelbaum F R. Prognostic impact of monosomalkaryotype in young adult and elderly acute myeloid leukemia: the SouthwestOncology Group (SWOG) experience. Blood, 2010, 116(13): 2224–2228
PMID: 20562328
Byrd J C, Mrózek K, Dodge R K, Carroll A J, Edwards C G, Arthur D C, Pettenati M J, Patil S R, Rao K W, Watson M S, Koduru P R, Moore J O, Stone R M, Mayer R J, Feldman E J, Davey F R, Schiffer C A, Larson R A, Bloomfield C D, 0. Pretreatment cytogeneticabnormalities are predictive of induction success, cumulative incidenceof relapse, and overall survival in adult patients with de novo acutemyeloid leukemia: results from Cancer and Leukemia Group B (CALGB8461). Blood, 2002, 100(13): 4325–4336
PMID: 12393746
Dash A, Gilliland D G. Molecular genetics of acute myeloid leukaemia. Best Pract Res Clin Haematol, 2001, 14(1): 49–64
PMID: 11355923
Mardis E R, Ding L, Dooling D J, Larson D E, McLellan M D, Chen K, Koboldt D C, Fulton R S, Delehaunty K D, McGrath S D, Fulton L A, Locke D P, Magrini V J, Abbott R M, Vickery T L, Reed J S, Robinson J S, Wylie T, Smith S M, Carmichael L, Eldred J M, Harris C C, Walker J, Peck J B, Du F, Dukes A F, Sanderson G E, Brummett A M, Clark E, McMichael J F, Meyer R J, Schindler J K, Pohl C S, Wallis J W, Shi X, Lin L, Schmidt H, Tang Y, Haipek C, Wiechert M E, Ivy J V, Kalicki J, Elliott G, Ries R E, Payton J E, Westervelt P, Tomasson M H, Watson M A, Baty J, Heath S, Shannon W D, Nagarajan R, Link D C, Walter M J, Graubert T A, DiPersio J F, Wilson R K, Ley T J. Recurring mutations found by sequencingan acute myeloid leukemia genome. N Engl J Med, 2009, 361(11): 1058–1066
PMID: 19657110
Chen J, Odenike O, Rowley J D. Leukaemogenesis: more thanmutant genes. Nat Rev Cancer, 2010, 10(1): 23–36
PMID: 20029422
Figueroa M E, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos P J, Schifano E, Booth J, van Putten W, Skrabanek L, Campagne F, Mazumdar M, Greally J M, Valk P J, L?wenberg B, Delwel R, Melnick A. DNA methylation signatures identify biologically distinctsubtypes in acute myeloid leukemia. Cancer Cell, 2010, 17(1): 13–27
PMID: 20060365
American Associationfor Cancer Research Human Epigenome Task Force; European Union, Networkof Excellence, Scientific Advisory Board. Moving AHEAD with an international human epigenome project. Nature, 2008, 454(7205): 711–715
PMID: 18685699
Li Z, Lu J, Sun M, Mi S, Zhang H, Luo R T, Chen P, Wang Y, Yan M, Qian Z, Neilly M B, Jin J, Zhang Y, Bohlander S K, Zhang D E, Larson R A, Le Beau M M, Thirman M J, Golub T R, Rowley J D, Chen J. Distinct microRNA expression profilesin acute myeloid leukemia with common translocations. Proc Natl Acad Sci U S A, 2008, 105(40): 15535–15540
PMID: 18832181
Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance ofFLT3 internal tandem duplication and tyrosine kinase domain mutationsfor acute myeloid leukemia: a meta-analysis. Leukemia, 2005, 19(8): 1345–1349
PMID: 15959528
Mead A J, Linch D C, Hills R K, Wheatley K, Burnett A K, Gale R E. FLT3 tyrosine kinase domain mutations are biologicallydistinct from and have a significantly more favorable prognosis thanFLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood, 2007, 110(4): 1262–1270
PMID: 17456725
Nerlov C. C/EBPalpha mutations in acute myeloid leukaemias. Nat Rev Cancer, 2004, 4(5): 394–400
PMID: 15122210
Pabst T, Mueller B U, Zhang P, Radomska H S, Narravula S, Schnittger S, Behre G, Hiddemann W, Tenen D G. Dominant-negative mutationsof CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha),in acute myeloid leukemia. Nat Genet, 2001, 27(3): 263–270
PMID: 11242107
Pabst T, Eyholzer M, Fos J, Mueller B U. Heterogeneity within AML with CEBPA mutations; only CEBPAdouble mutations, but not single CEBPA mutations are associated withfavourable prognosis. Br J Cancer, 2009, 100(8): 1343–1346
PMID: 19277035
Wouters B J, L?wenberg B, Erpelinck-Verschueren C A, van Putten W L, Valk P J, Delwel R. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acutemyeloid leukemia with a distinctive gene expression profile that isuniquely associated with a favorable outcome. Blood, 2009, 113(13): 3088–3091
PMID: 19171880
Borer R A, Lehner C F, Eppenberger H M, Nigg E A. Major nucleolar proteins shuttle between nucleus andcytoplasm. Cell, 1989, 56(3): 379–390
PMID: 2914325
Falini B, Bolli N, Liso A, Martelli M P, Mannucci R, Pileri S, Nicoletti I. Altered nucleophosmin transport in acute myeloid leukaemia with mutatedNPM1: molecular basis and clinical implications. Leukemia, 2009, 23(10): 1731–1743
PMID: 19516275
Schlenk R F, D?hner K, Krauter J, Fr?hling S, Corbacioglu A, Bullinger L, Habdank M, Sp?th D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, D?hner H, 0. Mutations and treatment outcome in cytogenetically normal acute myeloidleukemia. N Engl J Med, 2008, 358(18): 1909–1918
PMID: 18450602
Chou W C, Hou H A, Chen C Y, Tang J L, Yao M, Tsay W, Ko B S, Wu S J, Huang S Y, Hsu S C, Chen Y C, Huang Y N, Chang Y C, Lee F Y, Liu M C, Liu C W, Tseng M H, Huang C F, Tien H F. Distinct clinical and biologic characteristics in adult acute myeloidleukemia bearing the isocitrate dehydrogenase 1 mutation. Blood, 2010, 115(14): 2749–2754
PMID: 20097881
Wagner K, Damm F, G?hring G, G?rlich K, Heuser M, Sch?fer I, Ottmann O, Lübbert M, Heit W, Kanz L, Schlimok G, Raghavachar A A, Fiedler W, Kirchner H H, Brugger W, Zucknick M, Schlegelberger B, Heil G, Ganser A, Krauter J. Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphismin cytogenetically normal acute myeloid leukemia: SNP rs11554137 isan adverse prognostic factor. J Clin Oncol, 2010, 28(14): 2356–2364
PMID: 20368538
Paschka P, Schlenk R F, Gaidzik V I, Habdank M, Kr?nke J, Bullinger L, Sp?th D, Kayser S, Zucknick M, G?tze K, Horst H A, Germing U, D?hner H, D?hner K. IDH1 and IDH2 mutations arefrequent genetic alterations in acute myeloid leukemia and conferadverse prognosis in cytogenetically normal acute myeloid leukemiawith NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol, 2010, 28(22): 3636–3643
PMID: 20567020
Thol F, Damm F, Wagner K, G?hring G, Schlegelberger B, Hoelzer D, Lübbert M, Heit W, Kanz L, Schlimok G, Raghavachar A, Fiedler W, Kirchner H, Heil G, Heuser M, Krauter J, Ganser A. Prognostic impact of IDH2mutations in cytogenetically normal acute myeloid leukemia. Blood, 2010, 116(4): 614–616
PMID: 20421455
Chou W C, Hou H A, Chen C Y, Tang J L, Yao M, Tsay W, Ko B S, Wu S J, Huang S Y, Hsu S C, Chen Y C, Huang Y N, Chang Y C, Lee F Y, Liu M C, Liu C W, Tseng M H, Huang C F, Tien H F. Distinct clinical and biologic characteristics in adult acute myeloidleukemia bearing the isocitrate dehydrogenase 1 mutation. Blood, 2010, 115(14): 2749–2754
PMID: 20097881
Boissel N, Nibourel O, Renneville A, Gardin C, Reman O, Contentin N, Bordessoule D, Pautas C, de Revel T, Quesnel B, Huchette P, Philippe N, Geffroy S, Terre C, Thomas X, Castaigne S, Dombret H, Preudhomme C. Prognostic impact of isocitrate dehydrogenase enzymeisoforms 1 and 2 mutations in acute myeloid leukemia: a study by theAcute Leukemia French Association group. J Clin Oncol, 2010, 28(23): 3717–3723
PMID: 20625116
Marcucci G, Maharry K, Wu Y Z, Radmacher M D, Mrózek K, Margeson D, Holland K B, Whitman S P, Becker H, Schwind S, Metzeler K H, Powell B L, Carter T H, Kolitz J E, Wetzler M, Carroll A J, Baer M R, Caligiuri M A, Larson R A, Bloomfield C D. IDH1 and IDH2 gene mutationsidentify novel molecular subsets within de novo cytogenetically normalacute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol, 2010, 28(14): 2348–2355
PMID: 20368543
Ho P A, Alonzo T A, Kopecky K J, Miller K L, Kuhn J, Zeng R, Gerbing R B, Raimondi S C, Hirsch B A, Oehler V, Hurwitz C A, Franklin J L, Gamis A S, Petersdorf S H, Anderson J E, Reaman G H, Baker L H, Willman C L, Bernstein I D, Radich J P, Appelbaum F R, Stirewalt D L, Meshinchi S. Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study. Leukemia, 2010, 24(5): 909–913
PMID: 20376086
Beaupre D M, Kurzrock R. RAS and leukemia: from basic mechanisms to gene-directed therapy. J Clin Oncol, 1999, 17(3): 1071–1079
PMID: 10071302
Ritter M, Kim T D, Lisske P, Thiede C, Schaich M, Neubauer A. Prognostic significance of N-RAS and K-RAS mutationsin 232 patients with acute myeloid leukemia. Haematologica, 2004, 89(11): 1397–1399
PMID: 15531466
Radich J P, Kopecky K J, Willman C L, Weick J, Head D, Appelbaum F, Collins S J. N-ras mutations in adult de novo acute myelogenous leukemia: prevalenceand clinical significance. Blood, 1990, 76(4): 801–807
PMID: 2200539
Ernst P, Wang J, Korsmeyer S J. The role of MLL in hematopoiesisand leukemia. Curr Opin Hematol, 2002, 9(4): 282–287
PMID: 12042701
Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T, Büchner T, W?rmann B, Hiddemann W, Griesinger F. Screening for MLL tandem duplication in 387 unselected patients withAML identify a prognostically unfavorable subset of AML. Leukemia, 2000, 14(5): 796–804
PMID: 10803509
Whitman S P, Ruppert A S, Marcucci G, Mrózek K, Paschka P, Langer C, Baldus C D, Wen J, Vukosavljevic T, Powell B L, Carroll A J, Kolitz J E, Larson R A, Caligiuri M A, Bloomfield C D. Long-term disease-free survivorswith cytogenetically normal acute myeloid leukemia and MLL partialtandem duplication: a Cancer and Leukemia Group B study. Blood, 2007, 109(12): 5164–5167
PMID: 17341662
Yang L, Han Y, Suarez Saiz F, Saurez Saiz F, Minden M D. A tumor suppressor and oncogene: the WT1 story. Leukemia, 2007, 21(5): 868–876
PMID: 17361230
Paschka P, Marcucci G, Ruppert A S, Whitman S P, Mrózek K, Maharry K, Langer C, Baldus C D, Zhao W, Powell B L, Baer M R, Carroll A J, Caligiuri M A, Kolitz J E, Larson R A, Bloomfield C D. Wilms' tumor 1 gene mutations independently predict poor outcomein adults with cytogenetically normal acute myeloid leukemia: a cancerand leukemia group B study. J Clin Oncol, 2008, 26(28): 4595–4602
PMID: 18559874
Gaidzik V I, Schlenk R F, Moschny S, Becker A, Bullinger L, Corbacioglu A, Krauter J, Schlegelberger B, Ganser A, D?hner H, D?hner K, 0. Prognostic impact of WT1 mutations in cytogenetically normal acutemyeloid leukemia: a study of the German-Austrian AML Study Group. Blood, 2009, 113(19): 4505–4511
PMID: 19221039
Damm F, Heuser M, Morgan M, Yun H, Grosshennig A, G?hring G, Schlegelberger B, D?hner K, Ottmann O, Lübbert M, Heit W, Kanz L, Schlimok G, Raghavachar A, Fiedler W, Kirchner H, D?hner H, Heil G, Ganser A, Krauter J. Single nucleotide polymorphism in themutational hotspot of WT1 predicts a favorable outcome in patientswith cytogenetically normal acute myeloid leukemia. J Clin Oncol, 2010, 28(4): 578–585
PMID: 20038731
Becker H, Marcucci G, Maharry K, Radmacher M D, Mrózek K, Margeson D, Whitman S P, Paschka P, Holland K B, Schwind S, Wu Y Z, Powell B L, Carter T H, Kolitz J E, Wetzler M, Carroll A J, Baer M R, Moore J O, Caligiuri M A, Larson R A, Bloomfield C D. Mutations of the Wilms tumor 1 gene (WT1) in older patientswith primary cytogenetically normal acute myeloid leukemia: a Cancerand Leukemia Group B study. Blood, 2010, 116(5): 788–792
PMID: 20442368
Marcucci G, Maharry K, Radmacher M D, Mrózek K, Vukosavljevic T, Paschka P, Whitman S P, Langer C, Baldus C D, Liu C G, Ruppert A S, Powell B L, Carroll A J, Caligiuri M A, Kolitz J E, Larson R A, Bloomfield C D. Prognostic significance of,and gene and microRNA expression signatures associated with, CEBPAmutations in cytogenetically normal acute myeloid leukemia with high-riskmolecular features: a Cancer and Leukemia Group B Study. J Clin Oncol, 2008, 26(31): 5078–5087
PMID: 18809607
Green C L, Koo K K, Hills R K, Burnett A K, Linch D C, Gale R E. Prognostic significance of CEBPA mutations in a largecohort of younger adult patients with acute myeloid leukemia: impactof double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol, 2010, 28(16): 2739–2747
PMID: 20439648
Schnittger S, Kohl T M, Haferlach T, Kern W, Hiddemann W, Spiekermann K, Schoch C. KIT-D816 mutationsin AML1-ETO-positive AML are associated with impaired event-free andoverall survival. Blood, 2006, 107(5): 1791–1799
PMID: 16254134
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, 0, 0. Incidence and prognostic impact of c-Kit, FLT3,and Ras gene mutations in core binding factor acute myeloid leukemia(CBF-AML). Leukemia, 2006, 20(6): 965–970
PMID: 16598313
Neubauer A, Maharry K, Mrózek K, Thiede C, Marcucci G, Paschka P, Mayer R J, Larson R A, Liu E T, Bloomfield C D. Patients with acute myeloid leukemia and RAS mutations benefit mostfrom postremission high-dose cytarabine: a Cancer and Leukemia GroupB study. J Clin Oncol, 2008, 26(28): 4603–4609
PMID: 18559876
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 T A, Fitzgibbon J. Mutation of the Wilms' tumor 1 gene is a poor prognostic factor associated with chemotherapyresistance in normal karyotype acute myeloid leukemia: the UnitedKingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol, 2008, 26(33): 5429–5435
PMID: 18591546
Papadaki C, Dufour A, Seibl M, Schneider S, Bohlander S K, Zellmeier E, Mellert G, Hiddemann W, Spiekermann K. Monitoring minimal residual disease in acute myeloidleukaemia with NPM1 mutations by quantitative PCR: clonal evolutionis a limiting factor. Br J Haematol, 2009, 144(4): 517–523
PMID: 19055671
Bacher U, Badbaran A, Fehse B, Zabelina T, Zander A R, Kr?ger N. Quantitative monitoring ofNPM1 mutations provides a valid minimal residual disease parameterfollowing allogeneic stem cell transplantation. Exp Hematol, 2009, 37(1): 135–142
PMID: 19100523
Krauter J, Hoellge W, Wattjes M P, Nagel S, Heidenreich O, Bunjes D, Ganser A, Heil G. Detection and quantification of CBFB/MYH11 fusion transcripts in patients withinv(16)-positive acute myeloblastic leukemia by real-time RT-PCR. Genes Chromosomes Cancer, 2001, 30(4): 342–348
PMID: 11241787
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