Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia

Blood. 2012 Oct 25;120(17):3501-9. doi: 10.1182/blood-2012-02-414060. Epub 2012 Sep 5.


Stroma induces treatment resistance in chronic lymphocytic leukemia (CLL), possibly because of alterations in the BCL-2 family of proteins, which are key regulators of apoptosis. We previously developed BH3 profiling, a functional assay that assesses mitochondrial depolarization in response to BH3-only peptides, to measure "apoptotic priming," the proximity of a cell to the apoptotic threshold. In the present study, we use BH3 profiling to show that CLL cells from the PB are highly primed. Increased priming is associated with improved clinical response and, unexpectedly, with unmutated IGHV status. Coculturing CLL cells in vitro with stroma decreases priming. Using matched PB, BM, and lymph node compartment samples, we found in vivo that BM-derived CLL cells are the least primed. CLL cells cocultured with stroma were treated with the PI3K δ-isoform inhibitor CAL-101 (GS1101). CAL-101 caused CLL cell de-adhesion, leading to increased CLL cell priming. Stimulation of CLL cells with anti-IgM or CXCL12 caused decreased priming that could be reversed by CAL-101. Our results show that inhibition of stromal interactions leading to displacement of CLL cells into the blood by CAL-101 in vivo may increase CLL cell priming, suggesting a mechanism by which agents inducing lymphocyte redistribution might facilitate improved clinical response when used in combination with other therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Anti-Idiotypic / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / pathology
  • Cell Communication / drug effects
  • Cell Communication / immunology*
  • Chemokine CXCL12 / pharmacology
  • Coculture Techniques
  • Humans
  • Immunoglobulin M / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Lymph Nodes / drug effects
  • Lymph Nodes / pathology
  • Lymphocytes / drug effects
  • Lymphocytes / immunology*
  • Lymphocytes / pathology
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / immunology
  • Mitochondria / drug effects
  • Mitochondria / immunology*
  • Mitochondria / metabolism
  • Peptide Fragments / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins / pharmacology
  • Purines / pharmacology
  • Quinazolinones / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Stromal Cells / drug effects
  • Stromal Cells / immunology*
  • Stromal Cells / pathology
  • Tumor Cells, Cultured


  • Antibodies, Anti-Idiotypic
  • Bax protein (53-86)
  • Chemokine CXCL12
  • Immunoglobulin M
  • Peptide Fragments
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Purines
  • Quinazolinones
  • idelalisib