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DNA damage response as a biomarker in treatment of leukemias

H Dorota Halicka1, M Fevzi Ozkaynak, Oya Levendoglu-Tugal

  • 1Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY 10595, USA.

Cell Cycle (Georgetown, Tex.)
|May 5, 2009
PubMed

Insights

This study demonstrates the feasibility of assessing DNA damage response (DDR) in leukemia patients treated with DNA-targeting drugs. Measuring DDR biomarkers like ATM and H2AX phosphorylation shows potential for early treatment evaluation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Early assessment of cancer treatment response is crucial in clinical oncology.
  • DNA topoisomerase (topo) inhibitors are a common class of antitumor drugs targeting nuclear DNA.
  • DNA damage response (DDR) presents a potential biomarker for evaluating treatment efficacy.

Purpose of the Study:

  • To explore the feasibility of assessing DDR as a potential biomarker during the treatment of human leukemias.
  • To investigate the relationship between DDR and clinical response in leukemia patients.
  • To evaluate the utility of ATM and H2AX phosphorylation as indicators of DNA damage.

Main Methods:

  • Measured DDR by detecting ATM phosphorylation (ATM-S1981(P)) and histone H2AX phosphorylation (gammaH2AX).
  • Analyzed leukemic blast cells from 20 patients (16 children/adolescents, 4 adults) with acute leukemias.
  • Utilized phospho-specific antibodies and flow cytometry to quantify protein phosphorylation.
  • Collected blood samples one hour after drug infusion and compared to pre-treatment levels.

Main Results:

  • Observed an increase in ATM-S1981(P) and gammaH2AX levels in leukemic blasts post-treatment compared to pre-treatment.
  • Detected variations in the extent of DDR activation among individual patients.
  • Found a modest correlation between ATM activation and H2AX phosphorylation.
  • The study size was insufficient to establish prognostic value of DDR assessment.

Conclusions:

  • Demonstrated the feasibility of assessing DNA damage response (DDR) during leukemia treatment with DNA-targeting drugs.
  • ATM and H2AX phosphorylation are measurable indicators of DDR in response to topoisomerase inhibitors.
  • Further research with larger cohorts is needed to determine the clinical prognostic value of DDR assessment.

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