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Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance chemotherapy resistance in AML cells through a TGF-β-p38-ALDH2 pathway

ABSTRACT: Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance chemotherapy resistance in AML cells through a TGF-β-p38-ALDH2 pathway

PROVIDER: PRJNA641137 | ENA |

REPOSITORIES: ENA

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Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance chemotherapy resistance in AML cells through a TGF-β-p38-ALDH2 pathway

Project description:Our study aims to examine the interaction between AML cells and other cells in the tumor microenvironment, specifically bone marrow derived mesenchymal stromal cells. To delineate the specific genes/pathways involved in this interaction, we have co-cultured AML cell lines alone or with bone marrow derived mesenchymal stromal cells for 3 days, extracted total RNA from AML cells and analyzed the samples by RNA-seq. We identified the genes that are differentially expressed in co-cultured AML cells compared to AML cells alone. We found that TGF-β1 associated gene signature is activated in AML cells in the presence of BM-MSCs compared to AML cells alone.

2020-06-23 | GSE152996 | GEO

Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway.

Project description:The bone marrow microenvironment (BME) in acute myeloid leukemia (AML) consists of various cell types that support the growth of AML cells and protect them from chemotherapy. Mesenchymal stromal cells (MSCs) in the BME have been shown to contribute immensely to leukemogenesis and chemotherapy resistance in AML cells. However, the mechanism of stroma-induced chemotherapy resistance is not known. Here, we hypothesized that stromal cells promote a stem-like phenotype in AML cells, thereby inducing tumorigenecity and therapy resistance. To test our hypothesis, we co-cultured AML cell lines and patient samples with BM-derived MSCs and determined aldehyde dehydrogenase (ALDH) activity and performed gene expression profiling by RNA sequencing. We found that the percentage of ALDH+ cells increased dramatically when AML cells were co-cultured with MSCs. However, among the 19 ALDH isoforms, ALDH2 and ALDH1L2 were the only two that were significantly upregulated in AML cells co-cultured with stromal cells compared to cells cultured alone. Mechanistic studies revealed that the transforming growth factor-β1 (TGF-β1)-regulated gene signature is activated in AML cells co-cultured with MSCs. Knockdown of TGF-β1 in BM-MSCs inhibited stroma-induced ALDH activity and ALDH2 expression in AML cells, whereas treatment with recombinant TGF-β1 induced the ALDH+ phenotype in AML cells. We also found that TGF-β1-induced ALDH2 expression in AML cells is mediated by the non-canonical pathway through the activation of p38. Interestingly, inhibition of ALDH2 with diadzin and CVT-10216 significantly inhibited MSC-induced ALDH activity in AML cells and sensitized them to chemotherapy, even in the presence of MSCs. Collectively, BM stroma induces ALDH2 activity in AML cells through the non-canonical TGF-β pathway. Inhibition of ALDH2 sensitizes AML cells to chemotherapy.

| S-EPMC7703975 | biostudies-literature

PKCepislon-ALDH2 Pathway Plays a Novel Role in Adipocyte Differentiation

Project description:ALDH2 activator, Alda-1, is able to increase the catalytic activity of ALDH2. ALDH2 expression negatively correlates with obesity in mice while 4-HNE accumulation is positively associated with obesity and is increased in terminal adipocyte differentiation. We compared the difference of transcription profile between ethanol (EtOH)-treated and Alda-1-treated cells in induced adipocyte differentiation of 3T3-L1 pre-adipocytes.

2016-09-07 | E-MTAB-4936 | biostudies-arrayexpress

Molecular mechanism underlying increased ischemic damage in the ALDH2*2 genetic polymorphism using a human iPSC model system

Project description:We investigated the ALDH2*2 genetic polymorphism and its underlying mechanisms for the first time in a human model system of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from individuals carrying the most common heterozygous form of the ALDH2*2 genotype. We showed that the ALDH2*2 mutation confers elevated levels of reactive oxygen species (ROS) and toxic aldehydes such as 4HNE, thereby inducing cell cycle arrest and activation of apoptotic signaling pathways, especially during ischemic injury. ALDH2 exerts control of cell survival decisions via modulation of oxidative stress levels. This regulatory circuitry was found to be dysfunctional in the loss-of-function ALDH2*2 genotype, causing upregulation of apoptosis in cardiomyocytes following ischemic insult. These results reveal a novel function of the metabolic enzyme ALDH2 in modulation of cell survival decisions. Molecular mechanism of increased ischemic damage in cardiomyocytes of ALDH2*2 genotype.

2014-07-07 | E-GEOD-59100 | biostudies-arrayexpress

ALDH2 over expression in HCC cell line

Project description:mRNA levels of MHCCLM3 cell line over expressing ALDH2 and GFP were evaluated with Aligent microarray

2018-08-01 | GSE86060 | GEO

ALDH RNA seq

Project description:ALDH RNA seq

| PRJNA835897 | ENA

Expression data from ALDH− and ALDH+ shXIst0SUM159 cells treated with or without DOX

Project description:We used microarrays to identify differentially expressed miRNAs in ALDH− and ALDH+ cells treated with or without DOX

2023-08-02 | GSE222742 | GEO

Human colorectal cancer cell line CRC#21: ALDH-high cells vs. ALDH-low cells

Project description:Transcriptional profiling of cancer stem cells (ALDH-high cells) comparing non-cancer stem cells (ALDH-low cells), sorted out using ALDEFLUOR assay. Goal was to identity cancer stem cell-specific genes. Two-condition experiment, sphere-cultured cells vs. adherent-cultured cells: 1 ALDH-high replicate and 1 ALDH-low replicate.

2016-04-01 | E-GEOD-77149 | biostudies-arrayexpress

ALDH-positive MCF-7 cells

Project description:We used an Aldefluor assay system to study the signaling pathways that regulate the frequency and maintenance of ALDH-positive cell population in MCF-7 cells as a CSC model. Through microarray analysis, we investigated a possible receptor that increases the proportion of the ALDH-positive cell population in MCF-7 cells. MCF-7 were stained with Aldefluor and ALDH-positive cells were sorted using flow cytometry. Gene expression profiles of ALDH+ cells were compared with ALDH- cells.

2014-09-23 | E-GEOD-59653 | biostudies-arrayexpress

RNASeq analysis of human ALDH- and ALDH+ DU145 xenografts in nu/nu mice upon radiotherapy treatment

Project description:Purpose: we aimed at identify and compare the transcriptional changes of ALDH- and ALDH+ DU145 xenografts upon radiotherapy treatment. Method: Xenografts were generated by injection of ALDH- and ALDH+ DU145 cells in male NMRI-Foxn1 nu/nu immune-deficient mice and subjected to fractionated irradiation to a final dose of 50 Gy. Tumors were excised and processed for total RNA extraction and RNAseq analysis.

2022-01-22 | GSE193963 | GEO

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