Unexpected chronic lymphocytic leukemia B cell activation by bisphosphonates

Area of Science:

• Hematology
• Oncology
• Pharmacology

Background:

• Chronic lymphocytic leukemia (CLL) commonly affects the elderly and often co-occurs with osteoporosis, necessitating bisphosphonate (BP) treatment.
• Bisphosphonates (BPs) exhibit preclinical anticancer properties, suggesting potential therapeutic roles in malignancies.

Purpose of the Study:

• To investigate the in vitro effects of bisphosphonates (BPs) on chronic lymphocytic leukemia (CLL) B cells.
• To explore the concentration-dependent effects of BPs on CLL cell viability, apoptosis, and activation in a microenvironment-mimicking model.

Main Methods:

• In vitro study of CLL B cells activated by stimuli mimicking the tumor microenvironment.
• Assessment of BP effects at varying concentrations, including cytotoxicity, apoptosis modulation, and proliferation.
• Investigation of the role of stromal cells and soluble factors in BP-mediated effects on CLL cells.

Main Results:

• Bisphosphonates (BPs) exhibited hormetic effects on CLL B cells.
• Low-dose BPs protected CLL cells from spontaneous and chemotherapy-induced apoptosis while enhancing activation and proliferation.
• High-dose BPs induced cytotoxicity in CLL cells.
• The pro-leukemic effect of low-dose BPs was dependent on stromal cells and involved soluble factors and cell contact.

Conclusions:

• Bisphosphonates (BPs) can paradoxically promote chronic lymphocytic leukemia (CLL) cell activation and proliferation at low concentrations, potentially linked to poor prognostic markers.
• These findings highlight the complex, dose-dependent effects of BPs in the context of CLL and comorbidities like osteoporosis.
• Further investigation is warranted to understand the clinical implications of these findings for CLL patients undergoing BP therapy.