SRA

While the bone marrow (BM) microenvironment is significantly remodeled in acute myeloid leukemia (AML), our understanding of chemotherapy-induced changes within the BM stroma and their involvement in disease recurrence remains limited. Molecular insight into AML-specific alterations in the microenvironment has been historically limited by the analysis of liquid marrow aspirates rather than core biopsies that contain solid-phase BM stroma with non-hematopoietic cells supporting hematopoiesis. We assessed the effect of standard anthracycline- and cytarabine-based induction chemotherapy on both hematopoietic and non-hematopoietic cells directly in core BM biopsies using RNA-seq and histological analysis to determine the transcriptomic profile and factors associated with the response to treatment. We compared matched human core BM biopsies at diagnosis and 2 weeks after standard cytarabine/anthracycline induction therapy in responders (<5% blasts present post-treatment ) and non-responders (>5% blasts present post-treatment). Our data indicated enrichment in vimentin (VIM), platelet-derived growth factor receptor beta (PDGFRB) and Snail family transcriptional repressor 2(SNAI2) transcripts in responders, consistent with the reactivation of the mesenchymal population in the BM stroma. Enrichment of osteoblast maturation-related transcripts of biglycan (BGN), osteopontin (SPP1), and osteonectin (SPARC) was observed in core BM biopsies from non-responders to induction chemotherapy. To the best of our knowledge, this is the first report demonstrating distinct osteogenic and mesenchymal transcriptome profiles specific to AML BM response to induction chemotherapy assessed directly in core BM biopsies. Detailing treatment response-specific alterations in the BM stroma may inform optimized therapeutic strategies for AML. Overall design: Comparative gene expression profiling analysis of responders and non-responders to standard induction therapy in AML. Total mRNA was extracted from paired FFPE core bone marrow biopsies obtained at diagnosis (responder n=6/nonresponder n=5) and 2-weeks post- treatment (responder n=6/nonresponder n=5) induction.