Abstract IA08: The microenvironment in CLL: Cellular and molecular players and emerging therapeutic targets.

Abstract

Abstract The tissue microenvironment plays an important role of in the pathogenesis of chronic lymphocytic leukemia (CLL), delivering signals that promote the clonal expansion of the malignant B cells, as well as drug resistance. The complex cross talk between neoplastic B cells and the microenvironment, for example in secondary lymphoid organs, has been increasingly well characterized, and several cellular and molecular key players have emerged. Important cells in the CLL microenvironment are monocyte-derived nurselike cells (NLC), mesenchymal stromal cells (MSC), and T cells, which engage in a dialogue with the neoplastic CLL cells, often via specific receptor-ligand pairs. Engagement of CLL surface receptors by ligands in the tissue microenvironment, for example activation of B cell receptor (BCR) signaling, triggering of TNF family members (i.e. BAFF, APRIL), and activation of chemokine receptors and adhesion molecules result in the activation of signaling cascades that support the maintenance and expansion of the CLL clone. BCR signaling plays a particularly important pathogenic role in CLL, based on structural restrictions of the BCR, and signs of BCR-dependent survival and growth of the malignant B cells. Ligand-independent (“autonomous”) and ligand-dependent BCR signaling have been characterized, the latter triggered by (auto-) antigens present in the tissue microenvironment. Based on high response rates and durable remissions in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR-associated kinases (BTK, PI3Kδ), which currently are changing treatment paradigms in CLL. Clinical and translational aspects of these new targeted therapeutics will be discussed, along with an outlook into future therapeutic strategies. Citation Format: Jan A. Burger. The microenvironment in CLL: Cellular and molecular players and emerging therapeutic targets. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA08.