ArticleProceedings of the National Academy of Sciences of the United States of America2021
Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. 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, 32 citations in OpenAlex.
- Tuning of G-CSFR signaling by de novo-designed agonists.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Adjunctive effects of eltrombopag on immunosuppressive therapy for childhood aplastic anemia.International journal of hematology · 2025Article
- Cellular crosstalk in the bone marrow niche.Journal of translational medicine · 2024Review
- Cryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin.Nature communications · 2024Article
- JA(c)K-in-the-platelet and M(i)PL fetch PF4.Blood · 2024Article
- Single-nuclei transcriptome analysis of channel catfish spleen provides insight into the immunome of an aquaculture-relevant species.PloS one · 2024Article
- Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis.Cell · 2023Article
- Diagnosis- and Prognosis-Related Gene Alterations inInternational journal of molecular sciences · 2023Review
- Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia.Cancer discovery · 2023Article
- Article
- Molecular and cellular factors determining the functional pleiotropy of cytokines.The FEBS journal · 2023Review
- Oncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation.Nature communications · 2023Article
- The Involvement of Canonical NFκB Pathway in Megakaryocyte Differentiation Induction by Nanocurcumin.International journal of hematology-oncology and stem cell research · 2023Article
- Creation of Philadelphia chromosome by CRISPR/Cas9-mediated double cleavages on BCR and ABL1 genes as a model for initial event in leukemogenesis.Cancer gene therapy · 2023Article
- A marine sponge-derived lectin reveals hidden pathway for thrombopoietin receptor activation.Nature communications · 2022Article
- Single-chain tandem macrocyclic peptides as a scaffold for growth factor and cytokine mimetics.Communications biology · 2022Article
- In and out: Traffic and dynamics of thrombopoietin receptor.Journal of cellular and molecular medicine · 2021Review
- Review
Corrections and comments
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Authors and funding
17 authors at 5 institutions in 4 countries.
Funding
Abstract
Thrombopoietin (TPO) and the TPO-receptor (TPO-R, or c-MPL) are essential for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Agents that can modulate TPO-R signaling are highly desirable for both basic research and clinical utility. We developed a series of surrogate protein ligands for TPO-R, in the form of diabodies (DBs), that homodimerize TPO-R on the cell surface in geometries that are dictated by the DB receptor binding epitope, in effect "tuning" downstream signaling responses. These surrogate ligands exhibit diverse pharmacological properties, inducing graded signaling outputs, from full to partial TPO agonism, thus decoupling the dual functions of TPO/TPO-R. Using single-cell RNA sequencing and HSC self-renewal assays we find that partial agonistic diabodies preserved the stem-like properties of cultured HSCs, but also blocked oncogenic colony formation in essential thrombocythemia (ET) through inverse agonism. Our data suggest that dampening downstream TPO signaling is a powerful approach not only for HSC preservation in culture, but also for inhibiting oncogenic signaling through the TPO-R.
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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.