Evaluation of the Redox Profiles of Healthy and Pathological B Cells in Patients With Chronic Lymphocytic Leukemia

In recent years, considerable progress has been made in understanding the biology of chronic lymphocytic leukemia (CLL), resulting in the emergence of new therapeutic agents that have significantly improved the long-term survival of patients. However, LLC is still considered an incurable disease.

Cytogenetic abnormalities are frequently found in this pathology. Some abnormalities are associated with a more aggressive disease and a poor prognosis. The deletion of chromosome 17p (del (17p)), in particular, makes leukemic cells more resistant to standard therapy. Chromosome 17p contains the Tumor Protein 53 gene (TP53) which encodes the tumor suppressor protein 53 (P53) protein. P53 plays a central role in the regulation of important cellular functions such as DNA damage response, cell cycle regulation, apoptosis, and drug sensitivity of chemotherapies. In patients with CLL, the loss of p53 function is a major factor of chemoresistance and is associated with an adverse prognosis. The deletion (17p) is observed in approximately 5 to 10% of patients with CLL. In contrast, mutations in the TP53 gene are observed in approximately 30% of patients with CLL. This means that about one-third of patients with CLL have p53 dysfunction. TP53 and / or del (17p) mutated LLC cells show marked mitochondrial dysfunction. This dysfunction is responsible for a deregulation of intracellular redox phenomena, leading to an increase in oxidative stress and an overproduction of reactive oxygen derivatives (ROS).

Dimethyl Ampal Thiolester (DIMATE) is an active, competitive and irreversible inhibitor of aldehyde dehydrogenases (ALDH) 1 and 3. In vitro, DIMATE eradicates human cells from acute myeloblastic leukemia (AML). In patients with CLL, current treatments, particularly effective, do not specifically target pathological B cells. This results in chronic B lymphopenia and hypogammaglobulinemias that provide severe long-term infections, which is the leading cause of death in patients with CLL.

Through this study, we will study, in vitro, the expression of ALDH 1, 3, 9 but also of glutathione (GSH) and ROS on tumor B lymphocytes and healthy patients carrying an LLC. Depending on the differences in expression observed, DIMATE could specifically eradicate leukemic lymphocyte cells by sparing healthy lymphocytes, a hypothesis that will be tested in vitro. A special evaluation will be made in patients with del (17) and / or TP53 mutation whose prognosis is still considered unfavorable despite new therapeutic advances.