Refining the Diagnosis and Prognostic Categorization of Acute Myeloid Leukemia Patients with an Integrated Use of Cytogenetic and Molecular Studies

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]  R. Hills,et al.  Independent prognostic variables in acute myeloid leukaemia. , 2011, Blood reviews.

[2]  R. Hills,et al.  Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. , 2010, Blood.

[3]  Bob Löwenberg,et al.  Review Articles (434 articles) , 2008 .

[4]  L. Shaffer,et al.  ISCN 2009 - An International System for Human Cytogenetic Nomenclature , 2009 .

[5]  C. Schiffer.  Molecular characterization of AML: a significant advance or just another prognostic factor? , 2008, Best practice & research. Clinical haematology.

[6]  A. Hagemeijer,et al.  Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  K. Döhner,et al.  Molecular characterization of acute myeloid leukemia , 2008, Haematologica.

[8]  T. Haferlach,et al.  Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients. , 2008, Blood.

[9]  C. Preudhomme,et al.  Cooperating gene mutations in acute myeloid leukemia: a review of the literature , 2008, Leukemia.

[10]  M. Caligiuri,et al.  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. , 2008, Blood.

[11]  T. Haferlach.  Molecular genetic pathways as therapeutic targets in acute myeloid leukemia. , 2008, Hematology. American Society of Hematology. Education Program.

[12]  J. Licht,et al.  Molecular characterization of acute myeloid leukemia and its impact on treatment , 2007, Current opinion in oncology.

[13]  M. E. King,et al.  Recent developments in acute myelogenous leukemia therapy. , 2007, The oncologist.

[14]  A. Mead,et al.  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. , 2007, Blood.

[15]  C. Bloomfield,et al.  Clinical outcome of de novo acute myeloid leukaemia patients with normal cytogenetics is affected by molecular genetic alterations: a concise review , 2007, British journal of haematology.

[16]  Brunangelo Falini,et al.  Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. , 2007, Blood.

[17]  C. Bloomfield,et al.  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? , 2007, Blood.

[18]  C. Bloomfield,et al.  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 , 2006, Leukemia.

[19]  Gerhard Ehninger,et al.  Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). , 2006, Blood.

[20]  Gerhard Ehninger,et al.  Prevalence and prognostic impact of NPM 1 mutations in 1485 adult patients with acute myeloid leukemia ( AML ) , 2006 .

[21]  Jean McGowan-Jordan,et al.  ISCN 2013 : an international system for human cytogenetic nomenclature (2013) : recommendations of the International Standing Committee on Human Cytogenetic Nomenclature , 2005 .

[22]  Stefan Fröhling,et al.  Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. , 2005, Blood.

[23]  J. Cayuela,et al.  Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. , 2005, Blood.

[24]  Paola Fazi,et al.  Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. , 2005, The New England journal of medicine.

[25]  S. Fröhling,et al.  Diagnostic value of fluorescence in situ hybridization for the detection of genomic aberrations in older patients with acute myeloid leukemia. , 2005, Haematologica.

[26]  S. Fröhling,et al.  CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  H. Cavé,et al.  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 , 2003, Leukemia.

[28]  M. Caligiuri,et al.  BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. , 2003, Blood.

[29]  D. Linch,et al.  Flt3 mutations and leukaemia , 2003, British journal of haematology.

[30]  Axel Benner,et al.  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. , 2002, Blood.

[31]  S. Fröhling,et al.  Comparison of cytogenetic and molecular cytogenetic detection of chromosome abnormalities in 240 consecutive adult patients with acute myeloid leukemia. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  M. Caligiuri,et al.  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. , 2001, Cancer research.

[33]  E. Macintyre,et al.  Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease , 1999, Leukemia.

[34]  H. Kaneko,et al.  Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. , 1996, Leukemia.