# Unexpected chronic lymphocytic leukemia B cell activation by bisphosphonates

## TL;DR

Bisphosphonates, used for osteoporosis, may unexpectedly activate chronic lymphocytic leukemia B cells, potentially worsening the disease.

## Contribution

The study reveals a novel hormetic effect of bisphosphonates on CLL B cells, promoting activation and proliferation at low concentrations.

## Key findings

- Low concentrations of bisphosphonates protect CLL B cells from apoptosis and enhance their activation.
- The protective and activating effects require the presence of stromal cells and involve soluble factors.
- This effect is linked to poor prognosis markers in CLL.

## Abstract

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, often presenting comorbidities like osteoporosis and requiring, in a relevant proportion of cases, treatment with bisphosphonates (BPs). This class of drugs was shown in preclinical investigations to also possess anticancer properties. We started an in vitro study of the effects of BPs on CLL B cells activated by microenvironment-mimicking stimuli and observed that, depending on drug concentration, hormetic effects were induced on the leukemic cells. Higher doses induced cytotoxicity whereas at lower concentrations, more likely occurring in vivo, the drugs generated a protective effect from spontaneous and chemotherapy-induced apoptosis, and augmented CLL B cell activation/proliferation. This CLL-activation effect promoted by the BPs was associated with markers of poor CLL prognosis and required the presence of bystander stromal cells. Functional experiments suggested that this phenomenon involves the release of soluble factors and is increased by cellular contact between stroma and CLL B cells. Since CLL patients often present comorbidities such as osteoporosis and considering the diverse outcomes in both CLL disease progression and CLL response to treatment among patients, illustrating this phenomenon holds potential significance in driving additional investigations.

The online version contains supplementary material available at 10.1007/s00262-023-03588-z.