Spatial-Temporal Analysis Revealed the Dynamic Changes of Leukemia Neighborhood After Receiving Pembrolizumab and Decitabine

Acute myeloid leukemia (AML) is a genetically heterogeneous disease that is characterized by abnormal clonal proliferation of myeloid progenitor cells found predominately within the bone marrow (BM) and blood. Recent studies suggest that genetic and phenotypic alterations in the BM microenvironment support leukemogenesis and allow leukemic cells to survive and evade chemotherapy-induced death. However, despite substantial evidence indicating the role of tumor-host interactions in AML pathogenesis, little is known about the complex microenvironment of the BM. To address this, we performed novel proteomic profiling of the non-cellular compartment of the BM microenvironment in AML patients (n=10) and age- and sex-matched healthy controls (n=10) using an aptamer-based, highly multiplexed, affinity proteomics platform (SOMAscan). We demonstrate that proteomic assessment of blood or RNA-sequencing of BM are suboptimal alternate screening strategies to determine the true proteomic composition of the extracellular compartment of the AML marrow microenvironment. Proteomic analysis showed 168 proteins significantly differed in abundance, with 91 proteins up-regulated and 77 proteins down-regulated in leukemic BM. A highly connected signaling network of cytokines and chemokines, including IL-8, was found to be the most prominent proteomic signature associated with AML in the BM microenvironment. We report the first description of significantly elevated levels of the myelosuppressive chemokine CCL23 (MPIF–1) in both AML and MDS patients and perform functional experiments supportive of a role in the suppression of normal hematopoiesis. This unique paired RNA-sequencing and proteomics dataset provides innovative mechanistic insights into AML and healthy aging and should serve as a useful public resource.