Atm gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression

Anna Guarini, Marilisa Marinelli, Simona Tavolaro, Emanuele Bellacchio, Monia Magliozzi, Sabina Chiaretti, Maria Stefania de Propris, Nadia Peragine, Simona Santangelo, Francesca Paoloni, Mauro Nanni, Ilaria del Giudice, Francesca Romana Mauro, Isabella Torrente, Robin Foà

Research output: Contribution to journalArticle

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Abstract

Background: The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. Design and Methods: Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cyto-genetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. Results: Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apopto-sis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. Conclusions: ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.

Original languageEnglish
Pages (from-to)47-55
Number of pages9
JournalHaematologica
Volume97
Issue number1
DOIs
Publication statusPublished - Jan 1 2012

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B-Cell Chronic Lymphocytic Leukemia
Transcriptome
Disease Progression
Point Mutation
Genes
Ligation
Ataxia Telangiectasia Mutated Proteins
Immunoglobulin Genes
Mutation
p53 Genes
Therapeutics
Fluorescence In Situ Hybridization
DNA Repair
High Pressure Liquid Chromatography
Gene Expression

Keywords

  • ATM
  • Chronic lymphocytic leukemia
  • Del11q
  • Gene expression profiling
  • MLPA

ASJC Scopus subject areas

  • Hematology

Cite this

Atm gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression. / Guarini, Anna; Marinelli, Marilisa; Tavolaro, Simona; Bellacchio, Emanuele; Magliozzi, Monia; Chiaretti, Sabina; de Propris, Maria Stefania; Peragine, Nadia; Santangelo, Simona; Paoloni, Francesca; Nanni, Mauro; del Giudice, Ilaria; Mauro, Francesca Romana; Torrente, Isabella; Foà, Robin.

In: Haematologica, Vol. 97, No. 1, 01.01.2012, p. 47-55.

Research output: Contribution to journalArticle

Guarini, A, Marinelli, M, Tavolaro, S, Bellacchio, E, Magliozzi, M, Chiaretti, S, de Propris, MS, Peragine, N, Santangelo, S, Paoloni, F, Nanni, M, del Giudice, I, Mauro, FR, Torrente, I & Foà, R 2012, 'Atm gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression', Haematologica, vol. 97, no. 1, pp. 47-55. https://doi.org/10.3324/haematol.2011.049270
Guarini, Anna ; Marinelli, Marilisa ; Tavolaro, Simona ; Bellacchio, Emanuele ; Magliozzi, Monia ; Chiaretti, Sabina ; de Propris, Maria Stefania ; Peragine, Nadia ; Santangelo, Simona ; Paoloni, Francesca ; Nanni, Mauro ; del Giudice, Ilaria ; Mauro, Francesca Romana ; Torrente, Isabella ; Foà, Robin. / Atm gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression. In: Haematologica. 2012 ; Vol. 97, No. 1. pp. 47-55.
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abstract = "Background: The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. Design and Methods: Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cyto-genetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. Results: Mutational screening of the ATM gene identified point mutations in 8/57 cases (14{\%}). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20{\%} of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6{\%}) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apopto-sis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. Conclusions: ATM alterations are present at diagnosis in about 25{\%} of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.",
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AU - Magliozzi, Monia

AU - Chiaretti, Sabina

AU - de Propris, Maria Stefania

AU - Peragine, Nadia

AU - Santangelo, Simona

AU - Paoloni, Francesca

AU - Nanni, Mauro

AU - del Giudice, Ilaria

AU - Mauro, Francesca Romana

AU - Torrente, Isabella

AU - Foà, Robin

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N2 - Background: The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. Design and Methods: Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cyto-genetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. Results: Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apopto-sis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. Conclusions: ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.

AB - Background: The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. Design and Methods: Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cyto-genetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. Results: Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apopto-sis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. Conclusions: ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.

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