title: ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression.
abstract: BACKGROUND
  The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease.
  
  
  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, cytogenetic 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 apoptosis 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.
authors: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy. rfoa@bce.uniroma1.it
authors: Anna
authors: A
authors: Guarini
authors: Marilisa
authors: M
authors: Marinelli
authors: Simona
authors: S
authors: Tavolaro
authors: Emanuele
authors: E
authors: Bellacchio
authors: Monia
authors: M
authors: Magliozzi
authors: Sabina
authors: S
authors: Chiaretti
authors: Maria Stefania
authors: MS
authors: De Propris
authors: Nadia
authors: N
authors: Peragine
authors: Simona
authors: S
authors: Santangelo
authors: Francesca
authors: F
authors: Paoloni
authors: Mauro
authors: M
authors: Nanni
authors: Ilaria
authors: I
authors: Del Giudice
authors: Francesca Romana
authors: FR
authors: Mauro
authors: Isabella
authors: I
authors: Torrente
authors: Robin
authors: R
authors: Foà
mesh_terms: D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D020440:Gene Duplication; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases