Pb1920: targeting the tumor microenvironment interactions in chronic lymphocytic leukemia using leukotriene inhibitors

Topic: 7. Chronic myeloid leukemia - Biology & Translational Research Background: Chronic Lymphocytic Leukemia (CLL) is one of the most frequent types of leukemia in the west, including the Nordic countries. CLL cells proliferate and survive in microenvironment niches where they receive growth and survival signals. Adhesion of tumor cells to stromal cells in such niches stimulates the activation of multiple singling pathways, including B-cell receptor (BCR) signaling which is required for tumor cell survival. Recently, irreversible BTK inhibitors, ibrutinib, acalabrutinib and zanubrutinib have been proven to inhibit malignant B-cell survival through hindering tumor-microenvironment interactions. However, despite this progress, response to treatment with BTK inhibitors, is inadequate in some patients and patients frequently develop resistance to treatment. This is in part due to the fact that CLL is a heterogenous disease where tumor cells utilize different strategies for migration and adhesion. Therefore, studies are required to identify multiple therapeutic targets to disrupt tumor-microenvironment interactions. Aims: 5-lipoxygenase (5-LOX) catalyzes the conversion of arachidonic acid to leukotrienes (LTs). We showed that inhibition of 5-LOX decreased adhesion of Mantle cell lymphoma (MCL) cells to the stromal cells. Here in this study, we seek to explore the role of 5-LOX pathway in tumor-microenvironment interaction in CLL. Methods: An established ex vivo co-culture model system mimicking tumor-microenvironment interactions seen in vivo used to study the adhesion of CLL cells to stromal cells in the presence of several 5-LOX inhibitors. Results: We showed that adhesion of CLL cells is reduced by 5-LOX inhibition in a group of CLL patients. Cluster analysis identified distinct groups of patients with different patterns of response to 5-LOX inhibitors demonstrating that mutation burden and microenvironment context may influence response to these inhibitors. Summary/Conclusion: Our results suggest that 5-LOX has potential as a putative novel therapeutic target for development of new strategies for treatment of CLL. Keywords: B cell chronic lymphocytic leukemia, Chronic lymphocytic leukemia