ArticleCancer research2011
Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase.
Article in Cancer research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 78 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
78 citing papers in PubMed, 1 synthesis or guideline pooled it, 132 citations in OpenAlex.
- HSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia.The Journal of clinical investigation · 2014Pooled it
- PANoptosis in the pathogenesis of myelodysplastic syndromes.Molecular oncology · 2026Review
- Chromatin rewiring of β-globin and MYC enhancers by TGF-β1 drives defective erythropoiesis.Nature communications · 2026Article
- Observational and Genetic Association of Myelodysplastic Syndromes (MDS) and Autoimmune Diseases in Adults.Mediators of inflammation · 2026Article
- Advances in the characterization of in vitro-generated red blood cells: from biophysical properties to functional applications.Stem cell research & therapy · 2025Review
- Novel agents and evolving strategies for anemia management in lower-risk myelodysplastic syndromes.Blood research · 2025Review
- Splicing of erythroid transcription factor is associated with therapeutic response in myelodysplastic syndromes.The Journal of clinical investigation · 2025Article
- Advances and challenges in the treatment of myelodysplastic syndromes.Experimental hematology & oncology · 2025Review
- Myelodysplastic Neoplasms (MDS): Pathogenesis and Therapeutic Prospects.Biomolecules · 2025Review
- Predictive value of TGF-β1 and SMAD-7 expression at diagnosis for treatment response in low-risk myelodysplastic syndrome.Biomolecules & biomedicine · 2025Article
- Emerging insights into epigenetics and hematopoietic stem cell trafficking in age-related hematological malignancies.Stem cell research & therapy · 2024Review
- CCL9/CCR1 axis-driven chemotactic nanovesicles for attenuating metastasis of SMAD4-deficient colorectal cancer by trapping TGF-Acta pharmaceutica Sinica. B · 2024Article
- Review
- Role of innate immunological/inflammatory pathways in myelodysplastic syndromes and AML: a narrative review.Experimental hematology & oncology · 2023Review
- Excessive serine from the bone marrow microenvironment impairs megakaryopoiesis and thrombopoiesis in Multiple Myeloma.Nature communications · 2023Article
- The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies.Bone research · 2023Review
- Review
- TGF-beta signal transduction: biology, function and therapy for diseases.Molecular biomedicine · 2022Review
- Targeting inflammation in lower-risk MDS.Hematology. American Society of Hematology. Education Program · 2022Article
- Luspatercept (RAP-536) modulates oxidative stress without affecting mutation burden in myelodysplastic syndromes.Annals of hematology · 2022Article
18 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issuedMantzaris, Giannis [corrected to Mantzaris, Ioannis]
Authors and funding
28 authors at 6 institutions in 2 countries.
Funding
Abstract
Even though myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, the molecular alterations that lead to marrow failure have not been well elucidated. We have previously shown that the myelosuppressive TGF-β pathway is constitutively activated in MDS progenitors. Because there is conflicting data about upregulation of extracellular TGF-β levels in MDS, we wanted to determine the molecular basis of TGF-β pathway overactivation and consequent hematopoietic suppression in this disease. We observed that SMAD7, a negative regulator of TGF-β receptor I (TBRI) kinase, is markedly decreased in a large meta-analysis of gene expression studies from MDS marrow-derived CD34(+) cells. SMAD7 protein was also found to be significantly decreased in MDS marrow progenitors when examined immunohistochemically in a bone marrow tissue microarray. Reduced expression of SMAD7 in hematopoietic cells led to increased TGF-β-mediated gene transcription and enhanced sensitivity to TGF-β-mediated suppressive effects. The increased TGF-β signaling due to SMAD7 reduction could be effectively inhibited by a novel clinically relevant TBRI (ALK5 kinase) inhibitor, LY-2157299. LY-2157299 could inhibit TGF-β-mediated SMAD2 activation and hematopoietic suppression in primary hematopoietic stem cells. Furthermore, in vivo administration of LY-2157299 ameliorated anemia in a TGF-β overexpressing transgenic mouse model of bone marrow failure. Most importantly, treatment with LY-2157199 stimulated hematopoiesis from primary MDS bone marrow specimens. These studies demonstrate that reduction in SMAD7 is a novel molecular alteration in MDS that leads to ineffective hematopoiesis by activating of TGF-β signaling in hematopoietic cells. These studies also illustrate the therapeutic potential of TBRI inhibitors in MDS.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.