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

Area of Science:

• Hematology
• Cancer Biology
• Molecular Biology

Background:

• Stromal interactions contribute to treatment resistance in chronic lymphocytic leukemia (CLL).
• The BCL-2 protein family regulates apoptosis and is implicated in CLL resistance.
• BH3 profiling is a functional assay measuring apoptotic priming, indicating a cell's proximity to apoptosis.

Purpose of the Study:

• To investigate the impact of stromal interactions on CLL cell apoptotic priming.
• To assess the effect of the PI3Kδ inhibitor CAL-101 on CLL cell priming in the context of stromal interactions.
• To explore the relationship between apoptotic priming, clinical response, and IGHV mutation status in CLL.

Main Methods:

• BH3 profiling was used to measure apoptotic priming in CLL cells from peripheral blood (PB), bone marrow (BM), and lymph nodes.
• CLL cells were cocultured with stroma in vitro and treated with CAL-101.
• Stimulation with anti-IgM or CXCL12 was used to mimic stromal interactions.

Main Results:

• CLL cells from PB exhibit high apoptotic priming, unexpectedly associated with unmutated IGHV and improved clinical response.
• In vivo, BM-derived CLL cells show the least priming, while stroma reduces priming in vitro.
• CAL-101 treatment induced CLL cell de-adhesion from stroma, increasing priming; this effect reversed priming decreases induced by anti-IgM or CXCL12.

Conclusions:

• Stromal interactions decrease CLL cell apoptotic priming, contributing to treatment resistance.
• CAL-101 promotes CLL cell de-adhesion from stroma, thereby increasing apoptotic priming.
• CAL-101 may enhance the efficacy of combination therapies by increasing CLL cell priming through lymphocyte redistribution.