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WHO Classification of Tumours
Overview: AML with gene mutations


In addition to translocations and inversions, specific gene mutations also occur in AML (Table 6.01). They include frequent mutations of fms-related tyrosine kinase 3 (FLT3), nucleo­phosmin (NPM1) and, less commonly, mutations of the CEBPA gene (encoding the CCAAT/enhancer binding protein-α), KIT, MLL, WT1, NRAS and KRAS. Alone or in combination, mutations of FLT3, NPM1 and CEBPA have been reported in patients with AML with a normal karyotype where they have prognostic significance in the context of most current therapies, although they may be seen in patients with abnormal karyotypes as well
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Mrózek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD (2007)
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 109: 431-48



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FLT3, located at 13q12, encodes a tyrosine kinase receptor that is involved in haematopoietic stem cell differentiation and proliferation. FLT3 is expressed on these progenitor cells as well as on the blast cells in most cases of AML. FLT3 mutations may occur with any AML type (20-40% of all cases) and in MDS, but are most common in AML with t(6;9) (p23;q34), acute promyelocytic leukaemia and AML with a normal karyotype

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Kottaridis PD, Gale RE, Linch DC (2003)
Flt3 mutations and leukaemia.
Br J Haematol 122: 523-38




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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 (2006)
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 20: 1295-7



. The two primary types of FLT3 mutations are internal tandem duplications (FLT3-ITD) within the juxtamembrane domain (75-80%) and mutations affecting codons 835 or 836 of the second tyrosine kinase domain (TKD) (20-35%). While FLT3 mutations may occur in association with recurrent cytogenetic abnormalities, such as t(6;9)(p23;q34) and t(15;17)(q22;q12), they may also occur with other so-called cooperating mutations. FLT3-ITD mutations are associated with an adverse outcome, but the significance of the less common FLT3-TKD mutations remains controversial
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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: 2527-37




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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: 1262-70




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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: 1552-9



. Detection of FLT3-ITD is important because the prognosis of most cytogenetically normal AML subtypes correlates with the presence or absence of this mutation. KIT, located at 4q11-12, is a member of the type III tyrosine kinase family and encodes a 145-kD transmembrane glycoprotein. Gain-of-function mutations of KIT occur in a variety of diseases, including gastrointestinal stromal tumours, germ cell tumours, mastocytosis and AML. Mutations of KIT have been shown to have prognostic significance among AML with t(8;21)(q22;q22) and inv(16)(p13.1q22)/ t(16;16)(p13.1;q22), in which they are associated with a poor prognosis
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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: 3904-11



. These KIT mutations most commonly occur within exon 8 and 17. To date, WT1 mutations have been shown to confer a poor prognosis in AML patients with a normal karyo­type
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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: 4595-602



, but there is less compelling evidence of prognostic significance for the less frequent mutations of MLL, NRAS and KRAS. Molecular studies have shown that the MLL gene is rearranged more frequently than is revealed by conventional cytogenetic studies. A partial tandem duplication of MLL has been reported in 5-10% of adults with a normal karyotype
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Caligiuri MA, Strout MP, Lawrence D, Arthur DC, Baer MR, Yu F, Knuutila S, Mrózek K, Oberkircher AR, Marcucci G, de la Chapelle A, Elonen E, Block AW, Rao PN, Herzig GP, Powell BL, Ruutu T, Schiffer CA, Bloomfield CD (1998)
Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics.
Cancer Res 58: 55-9




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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 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the Acute Myeloid Leukemia Study Group Ulm.
J Clin Oncol 20: 3254-61



and in patients with isolated trisomy 11
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Caligiuri MA, Strout MP, Schichman SA, Mrózek K, Arthur DC, Herzig GP, Baer MR, Schiffer CA, Heinonen K, Knuutila S, Nousiainen T, Ruutu T, Block AW, Schulman P, Pedersen-Bjergaard J, Croce CM, Bloomfield CD (1996)
Partial tandem duplication of ALL1 as a recurrent molecular defect in acute myeloid leukemia with trisomy 11.
Cancer Res 56: 1418-25



. Its adverse prognostic significance in patients with a normal karyo­type is reported to be eliminated in patients receiving an autologous stem cell transplant in first remission
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Whitman SP, Ruppert AS, Marcucci G, Mrózek K, Paschka P, Langer C, Baldus CD, Wen J, Vukosavljevic T, Powell BL, Carroll AJ, Kolitz JE, Larson RA, Caligiuri MA, Bloomfield CD (2007)
Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study.
Blood 109: 5164-7



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NPM1 mutations occur in about one third of adult AML and CEBPA mutations in 6-15% of all AML. NPM1 mutations are typically heterozygous and the leukaemia cells retain a wild-type allele

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Falini B, Nicoletti I, Martelli MF, Mecucci C (2007)
Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features.
Blood 109: 874-85



. They usually occur at exon 12 of the NPM1 gene
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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)
Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype.
N Engl J Med 352: 254-66



but rarely involve exon 9 or 11
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Albiero E, Madeo D, Bolli N, Giaretta I, Bona ED, Martelli MF, Nicoletti I, Rodeghiero F, Falini B (2007)
Identification and functional characterization of a cytoplasmic nucleophosmin leukaemic mutant generated by a novel exon-11 NPM1 mutation.
Leukemia 21: 1099-103



. About 40 mutation variants have been described
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Falini B, Nicoletti I, Martelli MF, Mecucci C (2007)
Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features.
Blood 109: 874-85



, the most common being mutation A, a TCTG tetranucleotide duplication at positions 956 to 959, which accounts for 70-80% of adult AML with NPM1 mutation. Independent of type, NPM1 mutations generate common alterations at the C-terminus of NPM in leukaemic mutants, i.e. replacement of tryptophan(s) at position 288 and 290 and creation of a nuclear export signal (NES) motif, which mediates aberrant localization of NPM to the cytoplasm
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Falini B, Nicoletti I, Martelli MF, Mecucci C (2007)
Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features.
Blood 109: 874-85



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CEBPA (CCAAT/enhancer-binding protein-α) mutations occur only in AML and are usually biallelic mutations. The normal gene encodes a transcription factor involved in control of proliferation and differentiation of myeloid progenitors. While mutations may occur throughout the whole gene sequence, two general categories of mutation occur: out-of-frame insertions and deletions in the N-terminal region and in-frame insertions and deletions in the ­ C-terminal region. Mutations of NPM1 and CEBPA are frequently observed in AML with a normal karyotype and, in the absence of FLT3-ITD, are associated with a favourable prognosis

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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: 1416-24




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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: 3740-6




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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: 3733-9




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Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M, Ehninger G (2006)
Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML).
Blood 107: 4011-20




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Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W, Uitterlinden AG, Erpelinck CA, Delwel R, Löwenberg B, Valk PJ (2005)
Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance.
Blood 106: 3747-54



. In view of the frequency of these mutations, their prognostic significance, and their association with certain morphologic and clinical features, it has been suggested that they may identify unique subsets of AML. Therefore, two new provisional entities, AML with mutated NPM1 and AML with mutated CEBPA are proposed. These have been given provisional status because they have been only recently described and more study is required to confirm these categories as disease entities rather than prognostic factors. A small number of AML will show both NPM1 and CEBPA mutations, which would not fit well into the proposed classification structure. In addition, the prognostic significance of the chromosome aberrations reported to occur in 5-15% of AML with NPM1 or CEBPA mutations is not yet clear. Therefore, the presence of any of the recurrent translocations or inversions should be identified in any AML diagnosis. In addition, because of the adverse prognostic impact of FLT3 mutations in AML with NPM1 mutations, mutation analysis of FLT3 should always be performed with NPM1 and CEBPA.

These mutations are not detectable by cytogenetic analysis and are usually detected by PCR. Detection of cytoplasmic NPM by immunohistochemistry correlates well with the molecular method

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Falini B, Martelli MP, Bolli N, Bonasso R, Ghia E, Pallotta MT, Diverio D, Nicoletti I, Pacini R, Tabarrini A, Galletti BV, Mannucci R, Roti G, Rosati R, Specchia G, Liso A, Tiacci E, Alcalay M, Luzi L, Volorio S, Bernard L, Guarini A, Amadori S, Mandelli F, Pane F, Lo-Coco F, Saglio G, Pelicci PG, Martelli MF, Mecucci C (2006)
Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia.
Blood 108: 1999-2005



, but similar immunohistochemical surrogate tests are not currently available for all known mutations.







Daniel A. Arber
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Daniel A. Arber
Stanford University Medical Center
Stanford
USA




Richard D. Brunning
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Richard D. Brunning
Department of Laboratory Medicine and Pathology
University of Minnesota
Minneapolis
USA




Michelle M. Le Beau
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Michelle M. Le Beau
Cancer Cytogenetics Laboratory
University of Chicago
Chicago
USA




Brunangelo Falini
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Brunangelo Falini
Institute of Haematology
University of Perugia Policlinico Monteluce
Perugia
Italy




James W. Vardiman
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James W. Vardiman
Department of Pathology
University of Chicago Medical Center
Chicago
USA




Anna Porwit
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Anna Porwit
Department of Pathology
Karolinska University Hospital
Stockholm
Sweden




Jürgen Thiele
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Jürgen Thiele
Institute of Pathology
University of Cologne
Cologne
Germany




Clara D. Bloomfield
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Clara D. Bloomfield
The Ohio State University
519 James Cancer Hospital
Columbus
USA