Abstract A38: Remodeling of the malignant bone marrow niche represents a therapeutic target.

Abstract

Abstract Myeloproliferative neoplasms (MPNs) are malignant diseases of the hematopoietic stem cell (HSC). Targeting driver mutations in these diseases has had variable success. In chronic myelogenous leukemia (CML), targeting the BCR/ABL pathway has completely changed the way these patients are treated; however, there still remain a significant proportion of patients who have no targetable mutation for therapy and treatments centered on non-cell autonomous pathways of disease progression may have significant value. Previously, our lab showed that malignant myeloid cells from a mouse model of CML overexpressing BCR/ABL (BA mice) expand a remodeled mesenchymal stem cell (MSC) derived osteoblast population which leads to a fibrotic bone marrow (BM) niche and preserves malignant hematopoiesis (Schepers et al. Cell Stem Cell 2013; 13: 285-299). Disrupting the establishment of this fibrotic niche hopefully could delay clinical MPN progression and restore normal hematopoiesis. Bisphosphonates are known to act locally in the BM microenvironment on many cell types and improve the survival of patients with BM-involved disease, including multiple myeloma and breast cancer (Modi and Lentzsch. Leukemia 2012; 26:589-594). The focus of our current studies is to test the effect of zoledronic acid (ZA), a widely used bisphosphonate, on in vitro MSC fibrotic colony formation induced by malignant CML cells. Using whole BM from BA or control mice co-cultured with wild type MSCs, we found that ZA potently inhibited the increase in MSC colony formation induced by CML cells. The significant four-fold increase in MSC colony size (measured by cell number per colony) in BA co-cultures was completely negated by ZA at concentrations as low as 500 nM. The BA co-cultures were exquisitely sensitive to ZA and no breakthrough colonies were seen as compared to a 65 percent reduction in colony size in control co-cultures with 500 nM ZA. Our results suggest that zoledronic acid could be an interesting therapeutic compound to target the fibrotic BM niche in MPNs. Ongoing studies seek to understand the mechanism of action of ZA and to test its efficacy in preventing fibrosis and restoring a healthy BM niche in the BA model of CML. The goal is also to expand these results to other, more strongly fibrotic, mouse models of MPNs and human MPN samples. Citation Format: Timothy B. Campbell, Emmanuelle Passegué. Remodeling of the malignant bone marrow niche represents a therapeutic target. [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 A38.