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The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia

Linda Zuurbier1, Emanuel F Petricoin, Maartje J Vuerhard

  • 1Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands.

Haematologica
|April 12, 2012
PubMed
Abstract

Insights

Mutations in the PI3K/AKT pathway occur in 18% of pediatric T-cell acute lymphoblastic leukemia. These aberrations, often lacking strong NOTCH1 activation, are linked to a lower relapse rate, suggesting therapeutic implications.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pediatric Hematology

Background:

  • Phosphoinositide 3-kinase (PI3K)/AKT pathway mutations are implicated in T-cell acute lymphoblastic leukemia (T-ALL).
  • The role of PTEN mutations, potentially secondary to NOTCH1 mutations, in conferring resistance to γ-secretase inhibitors is under investigation.

Purpose of the Study:

  • To investigate the impact and associations of PTEN, PI3K, and AKT aberrations in pediatric T-ALL.
  • To correlate these genetic alterations with clinical outcomes and other genetic mutations.

Main Methods:

  • Analysis of a cohort of 146 pediatric T-ALL patients treated on DCOG or COALL protocols.
  • Genetic characterization including detection of PTEN and AKT E17K aberrations, and assessment of NOTCH1-activating mutations.

Main Results:

  • PTEN and AKT E17K aberrations were found in 13% and 2% of patients, respectively.
  • PTEN/AKT mutations were associated with TAL- or LMO-rearranged leukemia and inversely correlated with TLX3-rearranged leukemia.
  • Patients with PTEN/AKT and/or NOTCH1 mutations had a significantly higher cumulative incidence of relapse (35%) compared to those without (8%).

Conclusions:

  • PI3K/AKT pathway aberrations are present in 18% of pediatric T-ALL.
  • The absence of strong NOTCH1-activating mutations in these cases may contribute to cellular insensitivity to γ-secretase inhibitors.

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