Dataset Information

Targeting mesenchymal stromal cells plasticity to reroute acute myeloid leukemia course

ABSTRACT: MSC and AML dual targeting to treat pediatric AML Bone marrow (BM) microenvironment supports the regulation of normal hematopoiesis through a finely tuned balance of self-renewal and differentiation processes, cell-cell interaction and secretion of cytokines that during leukemogenesis are severely compromised and favor tumor cell growth. In pediatric acute myeloid leukemia (AML), chemotherapy is the standard of care, but still >30% of patients relapse. The need to accelerate the evaluation of innovative medicines prompted us to investigate the mesenchymal stromal cell (MSCs) role in the leukemic niche to define its contribution to the mechanisms of leukemia escape. We generated humanized three-dimensional (3D) niche with AML cells and MSCs derived from patients (AML-MSCs) or healthy donors. We observed that AML cells establish physical connections with MSCs, mediating a reprogrammed transcriptome inducing aberrant cell proliferation and differentiation, and severely compromising their immunomodulatory capability. We confirmed AML cells endow h-MSCs with a pro-oncogenic transcriptional profile and functions similar to the AML-MSCs when co-cultured in vitro. Conversely, MSCs derived from BM of patients at time of disease remission showed recovered healthy features, at transcriptional and functional levels, including the secretome. We sustained AML blasts altering MSC cell activities in the BM niche in order to favor disease development and progression, becoming a pharmacological target. We discovered that a novel AML-MSCs selective CaV1.2 channel blocker drug, Lercanidipine, is able to impair leukemia progression in 3D both, in vitro and when implanted in vivo, if used in combination with chemotherapy, supporting the hypothesis that synergistic effects can be obtained by dual targeting approaches.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169428 | GEO | 2021/07/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

Project description:Cyclic regeneration of the endometrium, and its repair after parturition or injury, are crucial for successful reproduction. Mesenchymal stem cells (MSCs) derived from bone marrow (BM-MSC) facilitate tissue repair via their secretome, which contains growth factors and cytokines that promote wound healing. Despite the implication of MSCs in endometrial regeneration and repair, the mechanisms remain unclear. This study tested the hypothesis that the secretome of MSCs from human BM upregulates human endometrial stromal cell (HESC) proliferation, migration and invasion, and activates pathways to increase HESC motility. MSCs were purchased from ATCC (BM-MSC-1) and cultured from the BM aspirate of a healthy female donor (BM-MSC-2). Indirect co-culture of MSCs and hTERT-immortalized HESCs via a transwell system studied the effect of the BM-MSC secretome on HESC proliferation, migration, and invasion. To study the effect of the MSC secretome on HESC gene expression, HESCs were exposed to the BM-MSC secretome via indirect co-culture for 24 h. Total RNA was extracted from HESCs for RNA sequencing (RNA-Seq). Differentially expressed genes (DEG) and significantly altered pathways were identified. Indirect co-culture of HESCs with BM- MSCs resulted in significant increase in HESC migration and invasion regardless of the source of MSCs. Effects on cellular proliferation varied among the BM-MSC source. Exposure of HESCs to the secretome of BM-MSCs changed the expression of 10,141 genes with FDR < 0.05. There was overlap among 4351 genes between HESCs exposed to BM-MSC-1 and BM-MSC-2, including upregulated expression of cell motility genes common to both BM-MSC exposures. Increased HESC motility by the secretome of BM-MSC appears to be mediated by paracrine and autocrine mechanisms, in part by modifying HESC gene expression. These data support the potential for leveraging the MSC secretome as a novel cell-free therapy in the treatment of disorders of endometrial regeneration.

Dataset Information

Targeting mesenchymal stromal cells plasticity to reroute acute myeloid leukemia course

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets