BioProject

Myeloid sarcoma is an aggressive extramedullary presentation of acute myeloid leukemia (AML) that may occur with or without medullary involvement. More...

Myeloid sarcoma is an aggressive extramedullary presentation of acute myeloid leukemia (AML) that may occur with or without medullary involvement. Here, we provide the first comprehensive profiling of myeloid sarcoma. We performed bulk RNA- and DNA-sequencing, as well as single-cell and spatial transcriptomic sequencing of myeloid sarcoma and AML with or without extramedullary disease (EMD), and show that EMD evolves from a pre-existing parental clone in the bone marrow (BM), is driven by increased clonal complexity and tumor mutation burden, and is enriched for RAS pathway mutations compared with AML. We further demonstrate unique transcriptional profiles in EMD that are suggestive of a gradual transition from liquid to a solid tumor environment, including activation of epithelial to mesenchymal transition (EMT)-like migration programs and down-regulation of inflammatory response genes. Our spatial profiling shows that myeloid sarcoma causes drastic tissue remodeling, activates EMT-like and RAS pathways, and is associated with the depletion of cytotoxic and effector T cells and increased regulatory T cells. We further identify substantial immune microenvironment remodeling, RAS pathway activation, and increased inflammation in the BM of patients with myeloid sarcoma, regardless of the presence or absence of concomitant medullary AML. This work provides a fundamental understanding of the pathogenesis of myeloid sarcoma and supports classifying myeloid sarcoma as a distinct myeloid neoplasm with overlapping but distinct evolutionary mechanisms from AML. Overall design: Tumor-derived RNA was subjected to 0.8x SPRI bead cleanup and size selection prior to DNase treatment and ribo-depletion prior to using the NEBNext Ultra II Directional kit preparation. The library was constructed for whole transcriptome sequencing (RNA-seq). Paired-end 151-bp reads were generated on the Illumina NovaSeq (Illumina, Inc.), and reads were aligned to the human genome reference sequence (GRCh38). Less...