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A specific subset of Mesenchymal Stromal Cells identified in poor prognosis pediatric AML favor leukemic stem cells persistence in the bone marrow [scRNA-seq]

ABSTRACT: Pediatric Acute Myeloid Leukemia (AML) emerge likely from highly complex, dynamic and multiparametric mechanism. The importance of stromal cells from the hematopoietic bone marrow (BM) microenvironment in early steps of pediatric AML (pAML) was explored in this study, based on samples of patients collected at diagnosis from a multicenter cohort (CONECT-AML). BM-Mesenchymal stem cells (BM-MSC) were isolated and characterized. Flow cytometry analysis revealed in more than a third of patients, the presence of a CD117(c-kit)-expressing sub-population of BM-MSC, rarely observed in healthy donors, associated with a higher LSC-17 score and a poor risk patient’s group. Lastly, single cell RNAseq data from pAML leukemic cells cocultured in a robust 3D-BM physio-pathological system built with CD117+ BM-MSC cells, indicate a high level of cell-cell interaction specific of this MSC. Very importantly, the presence of CD117+ BM-MSC significantly protect leukemic cells from chemotherapy killing trough cell-cell contacts. To summarize, we revealed the existence of a BM-MSC population associated with high risk pAML and that protect leukemic cells from treatments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275038 | GEO | 2025/12/05

REPOSITORIES: GEO

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Project description:Heterogeneity and variable survival outcomes of Acute Myeloid Leukemia (AML), suggest that yet undiscovered genes and pathways contribute to AML. Mesenchymal stem cells (MSC), an important component of bone marrow/ stromal microenvironment has been shown to contribute to development and progression of various cancers. Current study was aimed at characterizing MSC from AML bone marrow (BM) and evaluate their therapeutic potential in controlling survival of AML leukemic blasts. MSCs were isolated and cultured from BM of high-risk AML patients. MSC were also obtained from BM of bi-lineage leukemia (ETP-ALL) patients as control MSC from precursor stage of leukemia. MSC derived from uninvolved BM (UnBM) of lymphoma patients were used as normal MSC control. Leukemic blasts were derived from BM of AML and ETP-ALL patients. Patient derived AML-MSC exhibited characteristic profile of MSC Type-II CD90+CD45lo expressing high percent of TLR3 than TLR4 receptors, indicating pro-tumorigenic nature. Gene expression profiles of freshly derived leukemia blasts, AML cell line and AML MSC exhibited deregulated and overactivated Aurora Kinase pathway and inflammasome innate immune pathway. These two pathways are known to be upregulated in many solid and hematological cancers. Further we observed few tumor suppressor genes were downregulated in these groups. In vitro, AML MSC supported survival of leukemic blasts and increased chemoresistance to standard anticancer drugs. Hence AML MSC and ETP-ALL MSC were treated with immunomodulatory drug cocktail (IMiD) containing TLR3 antibody, TLR4 ligand and CXCR4 antagonist peptide (Gift from Kyoto University, Japan), designated as MSC-IMiD. It was observed that MSC-IMiD reduced chemoresistance of leukemic blasts to certain extent in vitro. Further we evaluated if leukemia BM derived MSC, MSC culture supernatant or MSC-IMiD can provide therapeutic benefit to control growth of AML xenograft in mouse model. Human gene expression profile was mapped in human-mouse xenograft made as subcutaneous tumor in immunodeficient NOD-SCID mice model from AML cell line KG1. Comparison was done of all treated groups with tumor bearing control gene expression data. It was interesting to note that MSC and MSC-IMiD could reduce tumor growth in 50% of mice tested. Mice treated with MSC culture supernatant exhibited reduction in tumor growth at par with that seen in Adriamycin treated positive control group. Deregulation of Aurora kinase pathway, inflammasome pathway genes and tumor suppressor genes was found to be reversed in residual tumor tissue of mice treated with MSC and MSC culture supernatant. This gene expression profiling study has helped understanding pathways involved in chemoresistance and immune suppression observed in AML. Moreover, this study has provided leads that MSC or its conditioned media can be explored further to control abnormal myelopoiesis in AML and develop targeted therapy. Funding source: Grant ID: 53/13/2013/CMB/BMS. Grantee: Jyoti Kode Grant title: Understanding the cross-talk between mesenchymal stromal cells and leukemic stem cells in Acute Myeloid Leukemia: Implications in disease biology and therapy. Name of the funding source: Indian Council of Medical Research, Government of India, India.

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A specific subset of Mesenchymal Stromal Cells identified in poor prognosis pediatric AML favor leukemic stem cells persistence in the bone marrow [scRNA-seq]

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