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Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation
09:02

Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation

Published on: November 26, 2018

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PI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression

Shuai Dong1,2, Bonnie K Harrington2,3, Eileen Y Hu2,4

  • 1Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy.

The Journal of Clinical Investigation
|November 21, 2018
PubMed

Insights

Genetic inactivation of PI3K p110δ delays leukemia in mice and reveals immune-modulatory effects. This inhibition impacts T cell responses and Treg function, suggesting broader therapeutic potential beyond direct anti-leukemic activity.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Targeted therapy with small molecule inhibitors, such as phosphatidylinositol-3'-kinase (PI3K) p110δ inhibitor idelalisib, has advanced leukemia treatment.
  • PI3K p110δ plays a critical role in B cell signaling and migration, crucial pathways in leukemia pathogenesis.

Purpose of the Study:

  • To investigate the role of PI3K p110δ in chronic lymphocytic leukemia (CLL) pathogenesis using a genetic inactivation model.
  • To explore the impact of p110δ inactivation on immune responses and its potential therapeutic implications in leukemia.

Main Methods:

  • Utilized the Eμ-TCL1 murine model of chronic lymphocytic leukemia (CLL) with genetic inactivation of p110δ (p110δD910A/D910A).
  • Assessed B cell receptor signaling, B cell migration, leukemia progression, and immune cell responses (T cells, Tregs) in genetically modified mice.
  • Investigated the effects of p110δ inactivation in the tumor microenvironment and its impact on leukemia resistance and T cell-mediated immunity.

Main Results:

  • Genetic inactivation of p110δ significantly delayed leukemia pathogenesis in the Eμ-TCL1 model.
  • p110δ inactivation led to rectal prolapse in mice, mirroring side effects seen with idelalisib treatment in humans.
  • Mice with inactivated p110δ showed impaired T cell responses but spontaneous recovery from leukemia, linked to impaired Treg expansion.
  • Reconstitution experiments confirmed the critical role of p110δ in Tregs for leukemia resistance.

Conclusions:

  • PI3K p110δ inhibition exhibits both direct anti-leukemic effects and indirect immune-activating properties.
  • p110δ blockade may possess broader immune-modulatory roles in various leukemia types, including those not directly sensitive to p110δ inhibition.
  • Understanding the immune-modulatory effects of p110δ inhibitors is crucial for optimizing their therapeutic application in leukemia.
Keywords:
B cellsHematologyImmunologyLeukemiasProtein kinases

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