ArticleBlood advances2019
Pharmacological DNA demethylation restores SMAD1 expression and tumor suppressive signaling in diffuse large B-cell lymphoma.
Article in Blood advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 24 citations in OpenAlex.
- Decitabine combined with RDHAP regimen in relapsed/refractory diffuse large B cell lymphoma.Cancer medicine · 2023Trial
- TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis.Cell death & disease · 2024Article
- FAT1 inhibits the proliferation of DLBCL cells via increasing the mScientific reports · 2024Article
- Biological signatures of the International Prognostic Index in diffuse large B-cell lymphoma.Blood advances · 2024Article
- Review
- BMP-ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B-Cell Lymphoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Loss of SMAD1 in acute myeloid leukemia withFrontiers in oncology · 2024Article
- Hypomethylating agent decitabine sensitizes diffuse large B-cell lymphoma to venetoclax.Haematologica · 2024Article
- Immune-depleted tumor microenvironment is associated with poor outcomes and BTK inhibitor resistance in mantle cell lymphoma.Blood cancer journal · 2023Article
- Article
- Sphingolipids and Lymphomas: A Double-Edged Sword.Cancers · 2022Review
- Transforming Growth Factor-Beta Orchestrates Tumour and Bystander Cells in B-Cell Non-Hodgkin Lymphoma.Cancers · 2022Review
- Article
- Clinical and Biological Subtypes of B-cell Lymphoma Revealed by Microenvironmental Signatures.Cancer discovery · 2021Article
- Genomic Landscape of Hodgkin Lymphoma.Cancers · 2021Review
- SMAD1 promoter hypermethylation and lack of SMAD1 expression in Hodgkin lymphoma: a potential target for hypomethylating drug therapy.Haematologica · 2021Article
- Epigenetic Mechanisms of Therapy Resistance in Diffuse Large B Cell Lymphoma (DLBCL).Current cancer drug targets · 2021Review
- DNA methyltransferases in hematological malignancies.Journal of genetics and genomics = Yi chuan xue bao · 2020Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The sphingosine-1-phosphate (S1P) receptor S1PR2 and its downstream adaptor Gα13 are recurrently mutationally inactivated in the germinal center B-cell subtype of diffuse large B-cell lymphoma (DLBCL) and are silenced by the S1PR2 repressor FOXP1 in the activated B-cell like subtype of the disease. Loss of S1PR2 signaling relieves the germinal center confinement that is maintained by an S1P gradient and allows cells to resist S1P-induced apoptosis. We have shown previously that S1PR2 expression is induced in normal B cells through a newly described transforming growth factor-β (TGF-β)/TGF-βRII/SMAD1 signaling axis that is inactivated in >85% of DLBCL patients. DLBCL cell lines lacking S1PR2, TGFBRII, or SMAD1 as the result of genomic editing all have a strong growth advantage in vitro, as well as in subcutaneous and orthotopic xenotransplantation models. Here, we show that the TGF-β signaling pathway in DLBCL is blocked at the level of SMAD1 in DLBCL cell lines and patient samples by hypermethylation of CpG-rich regions surrounding the SMAD1 transcription start site. The pharmacologic restoration of SMAD1 expression by the demethylating agent decitabine (DAC) sensitizes cells to TGF-β-induced apoptosis and reverses the growth of initially SMAD1- cell lines in ectopic and orthotopic models. This effect of DAC is reduced in a SMAD1-knockout cell line. We further show that DAC restores SMAD1 expression and reduces the tumor burden in a novel patient-derived orthotopic xenograft model. The combined data lend further support to the concept of an altered epigenome as a major driver of DLBCL pathogenesis.
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