Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway.
Aldehyde Dehydrogenase
/ genetics
Cell Line, Tumor
Cell Proliferation
/ drug effects
Coculture Techniques
Gene Expression Regulation, Neoplastic
/ drug effects
HEK293 Cells
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Mesenchymal Stem Cells
/ drug effects
Oxidoreductases Acting on CH-NH Group Donors
/ genetics
Signal Transduction
/ drug effects
Transforming Growth Factor beta1
/ genetics
Tumor Microenvironment
/ genetics
p38 Mitogen-Activated Protein Kinases
/ genetics
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
15
09
2020
accepted:
10
11
2020
entrez:
30
11
2020
pubmed:
1
12
2020
medline:
8
1
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33253299
doi: 10.1371/journal.pone.0242809
pii: PONE-D-20-26977
pmc: PMC7703975
doi:
Substances chimiques
TGFB1 protein, human
0
Transforming Growth Factor beta1
0
Aldehyde Dehydrogenase
EC 1.2.1.3
Oxidoreductases Acting on CH-NH Group Donors
EC 1.5.-
formyltetrahydrofolate dehydrogenase
EC 1.5.1.6
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0242809Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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