Abstract 1650: Bone marrow microenvironment control of BCL-6 in acute lymphocytic leukemia .

BCL-6 is a proto-oncogene that encodes for a BTB/POZ-zinc-finger transcriptional repressor, classically described in the regulation of germinal center (GC) formation. Relevant to the current study BCL-6 endows GCB-cells with enhanced proliferative capacity by protecting proliferating cells from DNA damage induced apoptosis through repression of p53 (Phan 2004) and through prevention of senescence by increasing the proliferative lifespan of B-cells (Shavarts 2002). BCL-6 also represses p53 in leukemic stem cells (Hurtz 2011) and is a key survival protein in Ph+ acute lymphoblastic leukemia (ALL) cells during kinase inhibition (Duy). Based on these observations the current study investigated potential bone marrow microenvironment (BMM) influence on BCL-6 in Ph+ and Ph- ALL as the site of initiation, progression, and often relapse of aggressive disease. Utilizing an in vitro model of tumor cells grown in media alone compared to tumor cells cultured with primary human osteoblasts (Promocell) or stromal cells we explored the effects of varied cues on BCL-6 expression. Co-culture experiments suggest that microenvironment derived signals decreased BCL-6 expression. We also noted decreased BCL-6 protein when tumor cells were exposed to Ara-C. Subsequently we evaluated long term co-culture experiments in which co-cultures of stroma/tumor or ostoeblast/tumor which had been grown together for 48hrs were challenged with chemotherapy for a period of 72 hrs. This resulted in tumors cells with less BCL-6 expression compared to non-treated co-culture controls. Chemotherapy treated co-cultures were provided drug free media every 5 days to simulate a recovery following cessation of therapy to determine if residual tumor cells survived the drug treatment and their capacity to repopulate the culture. Few tumor cells where seen in culture until days 15 to 20 post-treatment at which time cell number increased dramatically, coincident with high BCL-6 expression that subsequently decreased back to control levels at days 20-35. Tumor cells recovered at the termination of co-culture were uniformly CD38+. These results suggest that BCL-6 may be very responsive to a variety of cues in the context of chemotherapy exposure when a leukemic cell resides in the BMM, potentially supporting a quiescent drug resistant population of cells, in part, through down regulation of BCL-6. However, the effect is reversible as BCL-6 is restored during a phase of proliferative repopulation in a CD 38+ subset of cells. This scenario is reminiscent of the niche9s capacity to balance stem cell quiescence and proliferation during steady state hematopoiesis where stem and progenitor cells are drawn into cell cycle in a controlled manner. These preliminary observations suggest BCL-6 as a potentially important factor in maintaining quiescence and cell cycle entry in a leukemic model and draw clinical relevance based on the potential role of BCL-6 in relapse of ALL. Citation Format: William L. Slone, Zackary R. Lonergan, James Fortney, Debbie Piktel, Laura F. Gibson. Bone marrow microenvironment control of BCL-6 in acute lymphocytic leukemia . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1650. doi:10.1158/1538-7445.AM2013-1650