Expression data in bone marrow mesenchymal stromal cells derived from acute myeloid leukemia patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE122917 | GEO | 2021/11/26
REPOSITORIES: GEO
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Project description:Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the bone marrow (BM) stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Iradubicin (standard AML chemotherapy) by interfering with the BM stroma-mediated chemoresistance. We report that lenalidomide and pomalidomide have cytotoxic effects on neither AML cells nor BM-MSCs, but they increase the immunosuppressive/immunomodulatory properties of BM-MSCs. When combined with AraC and Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide highly mobilizes AML cells, but not healthy CD34+ cells, to peripheral blood (PB) likely through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize AML blasts to PB through downregulation of CXCR4 but do not improve AraC/Idarubicin activity in a preclinical model of AML.
2019-05-17 | GSE106748 | GEO
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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Project description: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.
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Project description:Acute Myeloid Leukemia (AML) is a heterogenous disease characterized by immature blasts at different maturation stage. We used single cell sequencing technique to analyze newly diagnosed AML patients.
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Project description:Bone marrow (BM) niche contributes to hematopoietic regeneration and can be remodeled by leukemic cells. We have found that Lama4 deletion in mouse mesenchymal stem cells (MSCs) could promote the proliferation of MLL-AF9 acute myeloid leukemia (AML) cells and chemoresistance of the cells to chemotherapy cytarabine. However, whether Lama4 deficient MSCs are more susseptible for AML cell remodeling remains to be explored. Here we report that differential molecular alterations in Lama4 deficient MSCs compared to wild type MSCs after being exposed to the AML cells for 48hours, which might be related to the enhanced AML cell proliferation and chemoresistance.
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Project description:Acute myeloid leukemia (AML) is one of the most common and deadly forms of hematopoietic malignancies. We hypothesized that microarray studies could identify aberrantly expressed genes selectively expressed in AML blasts, believing that these genes may be potential therapeutic targets for adoptive T-cell strategies We compared gene expression profiles between leukemic blasts from 30 AML patients (this series and GSE9476) and prepublished samples of normal hematopoietic cells from healthy donors (N=17, GSE9476) and testis samples (N=2, GSE1133).
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Project description:Acute myeloid leukemia (AML) is a highly heterogeneous disease and reliable detection of leukemic stem cells (LSCs) across genetic subclasses has proven difficult. We aimed to transcriptionally characterize LSCs specifically in monocyte-like AML (Mono-AML) and and primitive-like AML (Prim-AML) samples using cell surface markers. We used CD64+CD11b+ to define Mature blasts and labelled the rest as Immature. To further enrich for LSC-like cells in the Immature blasts in both Mono- and Prim-AML samples, we included GPR56, a marker for LSCs. We performed RNA sequencing on the FACS-sorted LSC-like and Mature cells from 23 AML patients.
2023-03-01 | E-MTAB-11976 | biostudies-arrayexpress
Project description:Inflammation in the bone marrow (BM) microenvironment is a constitutive component of acute myeloid leukemia (AML) pathogenesis. Studies have demonstrated that leukemic blasts propagate acute inflammation in the AML niche. Our recent studies in a congenic AML model suggest residual healthy hematopoietic stem and progenitor cells (HSPCs) participate in the inflammatory crosstalk. However, the underlying mechanism that drives the inflammatory conversion of HSPCs remains unclear. Here, we ask whether AML-derived extracellular vesicles (EV-AML) can convert HSPCs into an inflammatory active state in vivo. Using EV-AML purified from inducible (i)MLL-AF9 AML blasts (AF9-EV-AML), we challenged healthy C57BL/6J mice with serial injections of AF9-EVAML and analyzed HSPCs transcriptome. We show that HSPC transcriptome corroborates the enrichment of inflammatory and innate immune responses in EVAML-challenged BM HSPCs compared to controls. Our findings suggest that AML converts HSPCs into an inflammatory hub via EVAML in the AML niche.
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