Abstract LB-029: Identification of predictive genetic signatures of Cytarabine responsiveness in acute myeloid leukemia using a novel 3D translational culture model of primary bone marrow

Abstract

Abstract Acute myeloid leukemia (AML) is a malignancy with complex genetics, poor survival rates and high rates of chemotherapy resistance. This study reports the establishment of a novel bone marrow mononuclear cell 3D-culture model and the application of this model to define sensitivity and resistance biomarkers as evident by DNA and RNA expression signatures in response to standard Cytarabine (Ara-C) chemotherapy. By simulating the bone marrow microenvironment, we optimized the growth conditions using frozen bone marrow mononuclear cells (BMMC) derived from healthy donors. We validated our platform by demonstrating that healthy BMMCs are capable of differentiating into all hematopoietic lineages and various types of stromal cells. Using this platform, we then characterized BMMC samples from 47 AML patients. Sixty percent of AML samples were capable of proliferating and 23 samples demonstrated robust growth. RNA sequencing was performed for 3D and 2D cultures to determine which conditions are superior at maintaining original gene expression signatures as compared to the uncultured bone marrow, To elucidate specific genetic mutations and/or gene expression signatures associated with the ability of ex vivo growth of these AML donors, whole exosome sequencing and RNA Sequencing were performed. The model identified unique gene expression signatures that correlated with sensitive as well as resistant donors in response to Ara-C treatment. These data demonstrate the translational value of our platform which should be widely applicable to evaluate other therapies in AML. Citation Format: Haiyan Xu, Eric S. Muise, Sarah Javaid, Lan Chen, Razvan Cristescu, My Sam Mansueto, Nicole Follmer, Jennifer Cho, Kimberley Kerr, Rachel Altura, Michelle Machacek, Benjamin Nicholson, George Addona, Ilona Kariv, Hongmin Chen. Identification of predictive genetic signatures of Cytarabine responsiveness in acute myeloid leukemia using a novel 3D translational culture model of primary bone marrow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-029.