Transcriptomic analyse of mesenchymal stromal cells derived from bone marrow of patients with childhood acute lymphoblastic leukemia after interaction with leukemic blasts

Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by the abnormal expansion of clonal lymphoblasts in the bone marrow (BM). The behavior of malignant lymphoblasts is not only dependent on their genomic abnormalities but also, on their complex and reciprocal relationships with their local niche. BM microenvironment has a crucial role in the initiation and progression of leukemia. The implication of the bidirectional interaction between mesenchymal stromal cells (MSCs) and leukemic cells on growth and survival is still largely unknown and there is any study that shows the gene expression profiling in cocultured MSCs (with respect to monoculture conditions) on a transcriptome-wide basis. Taking all this into consideration, we have established cocultures between BM-derived MSCs and the leukemic blasts and performed microarray on the MSCs to determine deregulated genes due to the coculture condition with respect to MSCs in monoculture. We identified 293 differentially expressed genes (DEGs) in analyzing patient MSC (pMSC) samples vs. healthy MSC (hMSC) in co-culture condition and 861 DEGs of pMSC vs. hMSC analysis in monoculture condition and only 15 DEGs common in both groups. After bioinformatics and detailed data mining analysis, we have performed cluster analysis that shows a specific molecular signature of cocultured and monoculture MSCs. Then ontology and pathway analysis were performed. Results have shown 5 pathways of DEGs including axon guidance, ephrin signalling, FoxO signaling pathway, Wnt signaling pathway and signaling pathways regulating pluripotency of stem cells in coculture condition while 43 pathways of DEGs including pathways in cancer, TGFß signaling pathway, ECM-receptor interaction, p53 signaling pathway and PI3K-Akt signaling pathway in monoculture condition. Deregulated genes and pathways have showed that there is a communication between leukemic cells and MSCs, especially after coculture condition compared with the monoculture condition and genes and pathways linked to MSCs are related to axonogenesis and neurogenesis of which the importance is not yet understood in the leukemic bone marrow microenvironment. The elucidation of deregulated mechanisms and pathways provides new molecular insights to the contribution of these cells to ALL pathophysiology and understanding cross-talk between these cells may lead to founding new therapeutic targets. Keywords: Blast, childhood acute lymphoblastic leukemia, gene expression profile, mesenchymal stromal cell, microarray