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From a 2DE-Gel Spot to Protein Function: Lesson Learned From HS1 in Chronic Lymphocytic Leukemia
10:18

From a 2DE-Gel Spot to Protein Function: Lesson Learned From HS1 in Chronic Lymphocytic Leukemia

Published on: October 19, 2014

Current concepts: large granular lymphocyte leukemia

T Lamy1, T P Loughran

  • 1H. Lee Moffitt Cancer Center and the Veterans' Administration Hospital, Department of Internal Medicine, University of South Florida, Tampa, USA.

Blood Reviews
|March 31, 2000
PubMed

Insights

Large granular lymphocyte (LGL) leukemia, a clonal disorder affecting T-cells or NK-cells, often presents in elderly individuals with symptoms like neutropenia and anemia. Methotrexate can induce remission, but drug resistance is a challenge.

Area of Science:

  • Hematology
  • Immunology
  • Oncology

Background:

  • Large granular lymphocyte (LGL) disorders are clonal conditions originating from either T-cell or NK-cell lineages.
  • CD3+ T-cell LGL leukemia is the predominant form, typically affecting elderly patients.
  • Clinical manifestations include neutropenia, anemia, and rheumatoid arthritis, with T-cell LGL leukemia often presenting with a CD3+, alphabeta+, CD8+, CD57+ phenotype.

Purpose of the Study:

  • To elucidate the pathogenesis and clinical features of T-cell and NK-cell LGL leukemia.
  • To investigate the role of cytokines and apoptotic pathway defects in LGL leukemia.
  • To explore potential therapeutic strategies and resistance mechanisms in LGL leukemia.

Main Methods:

  • Analysis of LGL phenotypes (e.g., CD3, CD8, CD57).
  • Detection of clonality via T-cell receptor gene rearrangement.
  • Assessment of cytokine expression (IL12, IL15) and apoptotic pathway components (Fas, Fas-Ligand).
  • Evaluation of serologic reactivity (HTLV-I env p21e homology) and drug resistance markers (PgP+/LRP+).

Main Results:

  • T-LGL leukemia, the most common type, affects elderly individuals with symptoms like neutropenia and anemia.
  • NK-cell LGL disorders include aggressive NK LGL leukemia and chronic lymphocytosis.
  • Leukemic LGL cells exhibit resistance to Fas-induced apoptosis and constitutively express Fas/Fas-Ligand; soluble Fas-Ligand may cause neutropenia.
  • Reactivity to HTLV-I env p21e suggests a role for homologous proteins in pathogenesis.
  • Leukemic LGLs express multidrug resistance proteins (PgP+/LRP+), contributing to chemoresistance.

Conclusions:

  • LGL leukemia pathogenesis involves dysregulated apoptosis, potentially linked to cytokines like IL12/IL15 and defective Fas signaling.
  • Low-dose methotrexate can achieve clinical and molecular remission.
  • LGL leukemia serves as a model for understanding how dysregulated apoptosis contributes to malignancy and autoimmune diseases.
  • Multidrug resistance phenotype contributes to treatment challenges in aggressive cases.

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