Abstract LB050: Targeting cells in the microenvironment as a novel therapeutic strategy for chronic lymphocytic leukemia
Authors: Reyes Giovanna Merchand , Santhanam Ramasamy , Avila Frank H. Robledo , Weigel Christoph , Rosado Juan D. Ruiz , Mo Xiaokui , Sanchez Santiago Partida , Woyach Jennifer A. , Oakes Christopher C. , Tridandapani Susheela , Butchar Jonathan P. 
Published: June 2022

Abstract
Chronic lymphocytic leukemia (CLL) is a disease that affects the elderly, characterized by the accumulation of mature B cells in the bloodstream. With an estimation incidence of 21,250 new cases diagnosed and 4,320 deaths for 2021, CLL is still considered a non-curable disease despite the wide therapeutic alternatives. CLL, like other malignant diseases, involves the activity of different cells in the microenvironment that support the leukemic cells by providing survival signals, even in presence of therapeutic agents. Among these cells, nurse-like cells (NLC) are of great importance. NLCs are M2-like macrophages known to be developed from blood monocytes, which need close contact with CLL cells for both their differentiation and their protective function. They provide multiple survival signals to CLL cells, and protect them against agents like the BTK inhibitor ibrutinib. Despite their relevance, little research has been done to elucidate the program that drives NLC differentiation. Here, we addressed this question by looking at the DNA methylation signatures before and after NLC differentiation. We found that NLC differentiation produced a marked DNA hypomethylation when compared to freshly isolated monocytes, characterized by the enrichment in AP-1 transcription binding sites. AP-1 is known to be regulated by MAP kinases, so we decided to chemically inhibit these pathways and found that specific MEK inhibition lead to reduced numbers of NLCs in vitro. Further studies showed that indeed NLCs have an activated MEK signaling as seen by the basal phosphorylation of ERK in vitro by confocal microscopy. We then used the adoptive transfer Eµ-TCL1 mice model to seek the effect of MEK inhibition in vivo. By treating the mice with trametinib, an FDA-approved MEK inhibitor, we found an increase in mouse survival when compared with the vehicle control. In addition, we observed a reduced number of monocyte/macrophage populations, especially in those expressing EGR2, a known M2 marker, suggesting that MEK inhibition causes a disruption in CLL-supportive macrophages both in vitro and in vivo. In conclusion, we observed that NLC differentiation strongly depends on the MEK signaling pathway, and that its inhibition leads to reduced myeloid supportive cells for CLL cells, followed by a reduced leukemic progression and increased CLL survival in vivo. Thus, we propose that MEK inhibition could be a potential therapeutic alternative for CLL. Further research is ongoing to determine how MEK signaling is activated during NLC differentiation.
Citation Format: Giovanna Merchand Reyes, Ramasamy Santhanam, Frank H. Robledo Avila, Christoph Weigel, Juan D. Ruiz Rosado, Xiaokui Mo, Santiago Partida Sanchez, Jennifer A. Woyach, Christopher C. Oakes, Susheela Tridandapani, Jonathan P. Butchar. Targeting cells in the microenvironment as a novel therapeutic strategy for chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB050.