Mesenchymal Stromal Cells From AML Bone Marrow Are Abnormal by Gene Expression Profiling.

Abstract 1055

Cytogenetic and other evidence suggests that the mesenchymal stromal cell (MSC) is abnormal in bone marrow (BM) affected by acute myelogenous leukemia (AML). To gain further insight into molecular and physiologic abnormalities, we used Affymetrix HG-U133 Plus 2 microarrays to compare gene expression between BM-MSCs from 12 AML patients and BM-MSCs from 4 normal donors (ND). BM-MSCs were purified by in vitro culture as adherent cells with a purity of over 95%. Comparison at the single-gene level between AML and ND samples found only one differentially-expressed probe by t tests at a false-discovery rate (FDR) of 0.1. Comparison by the gene set enrichment analysis (GSEA) method of Subramanian et al., which is a more powerful way to find small differences that are significantly enriched within sets of biologically-related genes, first found that many enriched gene sets were predominantly the result of data from one AML sample. After excluding this sample, GSEA at an FDR of 0.25 found 115 downregulated gene sets for AML BM-MSCs from the Gene Ontology-based “C5” category of the mSigDB collection of gene sets. 19 of the 20 most significantly enriched downregulated gene sets were related to cell cycle progression, indicating that BM-MSCs are less proliferative in AML than in normal BM. An upregulated enriched gene set in AML BM-MSCs, from the “C2” category of curated gene sets, was composed of extracellular matrix genes for keratins, collagen, and laminin; while surprising, this is consistent with reports of BM-derived MSCs differentiating into epithelial cells after autografting, and suggest that BM-MSCs in AML may remodel the extracellular matrix. Overall, these results indicate that BM-MSCs in AML patients are substantially different from normal BM-MSCs. These and other differences could have substantial effects on the BM microenvironment and therapy response in AML, and should be studied further.