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Microarray analysis reveals that TP53- and ATM-mutant B-CLLs share a defect in activating proapoptotic responses

Tatjana Stankovic1, Mike Hubank, Debbie Cronin

  • 1Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, United Kingdom. t.stankovic@bham.ac.uk

Blood
|September 6, 2003
PubMed

Insights

The ATM/p53 DNA damage pathway is crucial in lymphoid tumors. ATM controls most transcriptional responses to DNA damage, including p53-independent survival signals, explaining why TP53-mutant B-cell lymphocytic leukemia is more aggressive.

Area of Science:

  • Molecular Biology
  • Cancer Genetics
  • Cellular Signaling

Background:

  • The ATM/p53 pathway is vital for DNA damage response and lymphoid tumor progression.
  • Inactivation of ATM or TP53 genes is common in B-cell lymphocytic leukemia (B-CLL), correlating with aggressive disease.
  • The functional overlap and differences between ATM and p53 pathways in tumor progression remain unclear.

Purpose of the Study:

  • To elucidate the distinct roles of ATM and p53 in the DNA damage response within B-CLL.
  • To compare the transcriptional profiles of B-CLLs with different ATM and TP53 genetic statuses.
  • To understand how ATM and p53 deficiencies contribute to B-CLL aggressiveness.

Main Methods:

  • Microarray analysis was employed to compare gene expression profiles.
  • ATM-mutant, TP53-mutant, and ATM/TP53 wild-type B-CLL samples were analyzed.
  • Transcriptional responses to DNA damage (irradiation) were assessed.

Main Results:

  • ATM function is essential for all transcriptional responses to DNA damage.
  • ATM regulates both proapoptotic (via p53) and prosurvival responses independently of p53.
  • TP53-mutant B-CLLs exhibit greater severity due to combined defective apoptosis and enhanced survival signaling post-DNA damage.
  • Transcriptional profiles are similar in ATM-deficient, TP53-deficient, and wild-type B-CLLs prior to DNA damage.

Conclusions:

  • ATM governs a broader spectrum of transcriptional responses to DNA damage than previously recognized.
  • The distinct roles of ATM and p53 explain differential B-CLL aggressiveness based on mutation status.
  • Damage-induced transcriptional fingerprinting offers a method for tumor stratification and identification of therapeutic targets.

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