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Mammalian target of rapamycin (mTOR) activity dependent phospho-protein expression in childhood acute lymphoblastic

Karolina Nemes1, Anna Sebestyén, Agnes Márk

  • 12nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.

Plos One
|April 11, 2013
PubMed

Insights

Measuring mTOR activity, specifically phosphorylated eukaryotic initiation factor 4E binding protein (p-4EBP1), in childhood acute lymphoblastic leukemia (ALL) can predict poor prognosis and detect relapses, guiding targeted therapy development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Childhood acute lymphoblastic leukemia (ALL) treatment has improved, but 25-30% of patients still face treatment failure.
  • Targeted therapies are crucial for improving outcomes in pediatric ALL.
  • Mammalian target of rapamycin (mTOR) kinase is a key signaling pathway mediator with potential as a therapeutic target in ALL.

Purpose of the Study:

  • To characterize mTOR kinase activity in pediatric ALL.
  • To evaluate mTOR activity-dependent phosphoproteins as potential biomarkers for prognosis and relapse.
  • To explore the utility of measuring mTOR activity for patient selection in future mTOR inhibitor therapies.

Main Methods:

  • Enzyme-linked immunosorbent assay (ELISA) was used to quantify mTOR activity-dependent phosphoproteins, including phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor 4E binding protein (p-4EBP1).
  • Measurements were performed on human leukemia cell lines and lymphoblasts from childhood ALL patients (n=49) at diagnosis, during chemotherapy, and at relapse.
  • Optical density (OD) values for p-4EBP1 were analyzed in relation to patient prognosis and treatment response.

Main Results:

  • Leukemia cell lines demonstrated increased mTOR activity, evidenced by elevated p-S6 and p-4EBP1 levels.
  • ALL patient samples at diagnosis showed elevated p-4EBP1 levels, which decreased with effective chemotherapy.
  • Higher p-4EBP1 OD values at diagnosis correlated with poor prognosis and were also observed in relapsed patients.

Conclusions:

  • ELISA measurement of mTOR activity-related phosphoproteins, particularly p-4EBP1, can aid in identifying pediatric ALL patients with poor prognosis prior to treatment.
  • This method may facilitate early detection of relapses in childhood ALL.
  • Assessing mTOR activity in leukemic cells could guide the selection of patients for future mTOR inhibitor treatments.

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