Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profiling

This study shows that gene expression profiling allows accurate prediction of certain acute myeloid leukemia subtypes, e.g. those characterized by expression of chimeric transcription factors. We examined the gene expression profiles of two independent cohorts of patients with acute myeloid leukemia [n=247 and n=214 (younger than or equal to 60 years)] to study the applicability of gene expression profiling as a single assay in prediction of acute myeloid leukemia-specific molecular subtypes. The favorable cytogenetic acute myeloid leukemia subtypes, i.e., acute myeloid leukemia with t(8;21), t(15;17) or inv(16), were predicted with maximum accuracy (positive and negative predictive value: 100%). Mutations in NPM1 and CEBPA were predicted less accurately (positive predictive value: 66% and 100%, and negative predictive value: 99% and 97% respectively). Various other characteristic molecular acute myeloid leukemia subtypes, i.e., mutant FLT3 and RAS, abnormalities involving 11q23, −5/5q-, −7/7q-, abnormalities involving 3q (abn3q) and t(9;22), could not be correctly predicted using gene expression profiling. In conclusion, gene expression profiling allows accurate prediction of certain acute myeloid leukemia subtypes, e.g. those characterized by expression of chimeric transcription factors. However, detection of mutations affecting signaling molecules and numerical abnormalities still requires alternative molecular methods.

[1]  B. Löwenberg,et al.  High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. , 2008, Blood.

[2]  Pu Zhang,et al.  Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. , 2007, Blood.

[3]  Claudio Lottaz,et al.  Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia , 2007 .

[4]  C. Bloomfield,et al.  Chromosome aberrations, gene mutations and expression changes, and prognosis in adult acute myeloid leukemia. , 2006, Hematology. American Society of Hematology. Education Program.

[5]  Bob Löwenberg,et al.  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. , 2005, Blood.

[6]  W. Hiddemann,et al.  Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. , 2005, Blood.

[7]  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.

[8]  W. Hiddemann,et al.  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Global approach to the diagnosis of leukemia using gene expression profiling , 2022 .

[9]  Natalia Meani,et al.  Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. , 2005, Blood.

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

[11]  E. Devilard,et al.  Identification of new classes among acute myelogenous leukaemias with normal karyotype using gene expression profiling , 2004, Oncogene.

[12]  R. Tibshirani,et al.  Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. , 2004, The New England journal of medicine.

[13]  R. Verhaak,et al.  Prognostically useful gene-expression profiles in acute myeloid leukemia. , 2004, The New England journal of medicine.

[14]  C. Bloomfield,et al.  Cytogenetics in Acute Leukemia , 2022 .

[15]  J. Reilly,et al.  Second hit mutations in the RTK/RAS signaling pathway in acute myeloid leukemia with inv(16). , 2004, Haematologica.

[16]  W. Hiddemann,et al.  Molecular characterization of acute leukemias by use of microarray technology , 2003, Genes, chromosomes & cancer.

[17]  J. Reilly,et al.  Incidence and prognosis of c‐KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias , 2003, British journal of haematology.

[18]  T. A. Lister,et al.  Genome‐wide analysis of acute myeloid leukemia with normal karyotype reveals a unique pattern of homeobox gene expression distinct from those with translocation‐mediated fusion events , 2003, Genes, chromosomes & cancer.

[19]  Bob Löwenberg,et al.  Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. , 2003, The hematology journal : the official journal of the European Haematology Association.

[20]  R. Eils,et al.  Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Tibshirani,et al.  Diagnosis of multiple cancer types by shrunken centroids of gene expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Caligiuri,et al.  Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics. , 2001, Proceedings of the National Academy of Sciences of the United States of America.