Abstract
Bone marrow-derived mesenchymal stromal cells (BM-MSCs) play a fundamental role in the BM microenvironment (BME) and abnormalities of these cells may contribute to acute myeloid leukemia (AML) pathogenesis. The aim of the study was to characterize the cytokine and gene expression profile, immunophenotype and cytogenetics of BM-MSCs from AML patients compared to normal BM-MSCs from healthy donors. AML BM-MSCs showed decreased monocyte chemoattractant protein-1 levels compared to normal BM-MSCs. AML BM-MSCs expressed similar β1 integrin, CD44, CD73, CD90 and E-cadherin compared to normal BM-MSCs. Cytogenetic analysis revealed chromosomal aberrations in AML BM-MSCs, some overlapping with and others distinct from their corresponding AML blasts. No significant difference in gene expression was detected between AML BM-MSCs compared to normal BM-MSCs; however, comparing the differences between AML and MSCs from AML patients with the differences between normal hematopoietic cells and normal MSCs by Ingenuity pathway analysis showed key distinctions of the AML setting: (1) upstream gene regulation by transforming growth factor beta 1, tumor necrosis factor, tissue transglutaminase 2, CCAAT/enhancer binding protein alpha and SWItch/Sucrose NonFermentable related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; (2) integrin and interleukin 8 signaling as overrepresented canonical pathways; and (3) upregulation of transcription factors FBJ murine osteosarcoma viral oncogene homolog and v-myb avian myeloblastosis viral oncogene homolog. Thus, phenotypic abnormalities of AML BM-MSCs highlight a dysfunctional BME that may impact AML survival and proliferation.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous disorder that arises in the bone marrow microenvironment (BME) under the influence of mesenchymal stromal cells (MSCs), endothelial cells, osteocytes, pericytes, adipocytes, monocytes, fibroblasts and their secreted extracellular glycosaminoglycans, chemokines and cytokines
We observed a trend toward reduced granulocyte-monocyte CSF (GM-CSF) and interleukin 6 (IL-6) levels produced by AML BM-derived MSCs (BM-MSCs) compared with BM-MSCs from healthy donors (P40.07)
We found significantly reduced monocyte chemoattractant protein-1 (MCP-1) levels from BM-MSCs from AML patients compared to BM-MSCs from healthy donors
Summary
Acute myeloid leukemia (AML) is a heterogeneous disorder that arises in the bone marrow microenvironment (BME) under the influence of mesenchymal stromal cells (MSCs), endothelial cells, osteocytes, pericytes, adipocytes, monocytes, fibroblasts and their secreted extracellular glycosaminoglycans, chemokines and cytokines. In a study of surgically resected hepatocellular carcinoma, the gene expression profile of the non-malignant peri-tumoral tissue in the resection specimen could predict disease relapse, whereas the expression profile of the malignant cells themselves did not.. In a study of surgically resected hepatocellular carcinoma, the gene expression profile of the non-malignant peri-tumoral tissue in the resection specimen could predict disease relapse, whereas the expression profile of the malignant cells themselves did not.11 These findings suggest that alteration in the surrounding stromal tissue independently contributed to disease behavior. Another study showed that an activating mutation of β-catenin in osteoblasts induced AML through Notch signaling.13 Considering these reports of stroma-microenvironment aberrations influencing the evolution of malignant conditions, we hypothesized that the BM-derived MSCs (BM-MSCs) from AML patients would exhibit distinct genotypic and phenotypic differences compared to BM-MSCs from normal healthy donors Work in mouse models have provided evidence that alterations in the BME can contribute to the evolution of hematologic malignancy: for example, knockout of the RNase III endonuclease Dicer in mesenchymal osteoprogenitor cells resulted in myelodysplasia and emergence of AML despite maintaining genetic integrity in the hematopoietic lineage. Another study showed that an activating mutation of β-catenin in osteoblasts induced AML through Notch signaling. Considering these reports of stroma-microenvironment aberrations influencing the evolution of malignant conditions, we hypothesized that the BM-derived MSCs (BM-MSCs) from AML patients would exhibit distinct genotypic and phenotypic differences compared to BM-MSCs from normal healthy donors
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