ArticleThe Journal of experimental medicine2016
Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression.
Article in The Journal of experimental medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 38 citations in OpenAlex.
- TGFβ signaling promotes cell cycle progression and resistance to the CDK4/6 inhibitor palbociclib through SOX4 transcriptional modulation in breast cancer cells.Cell death & disease · 2026Article
- Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling.Nature communications · 2025Article
- Dual PTCH2 mutation [Ser391*, Leu104Pro]: unveiling a potential new genetic susceptibility factor for glioma development.Investigational new drugs · 2025Article
- The Role of Mutated Calreticulin in the Pathogenesis ofInternational journal of molecular sciences · 2024Article
- Phosphatase, MgHaematologica · 2024Article
- Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms.Cell reports · 2024Article
- Transcriptomic Analysis Reveals JAK2/MPL-Independent Effects of Calreticulin Mutations in aCells · 2023Article
- Ptch2 is a Potential Regulator of Mesenchymal Stem Cells.Frontiers in physiology · 2022Article
- Murine Oncostatin M Has Opposing Effects on the Proliferation of OP9 Bone Marrow Stromal Cells and NIH/3T3 Fibroblasts Signaling through the OSMR.International journal of molecular sciences · 2021Article
- Minibrain-related kinase/dual-specificity tyrosine-regulated kinase 1B implication in stem/cancer stem cells biology.World journal of stem cells · 2020Review
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- Loss of the Fanconi anemia-associated protein NIPA causes bone marrow failure.The Journal of clinical investigation · 2020Article
- Bone marrow niches in haematological malignancies.Nature reviews. Cancer · 2020Review
- Elevated Hedgehog activity contributes to attenuated DNA damage responses in aged hematopoietic cells.Leukemia · 2020Article
- ATF3 Prevents Stress-Induced Hematopoietic Stem Cell Exhaustion.Frontiers in cell and developmental biology · 2020Article
- Hematopoietic Stem Cell Niches and Signals Controlling Immune Cell Development and Maintenance of Immunological Memory.Frontiers in immunology · 2020Review
- Targeting the Microenvironment in MDS: The Final Frontier.Frontiers in pharmacology · 2020Review
- Article
- New Concepts of Treatment for Patients with Myelofibrosis.Current treatment options in oncology · 2019Review
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
JAK2V617F(+) myeloproliferative neoplasms (MPNs) frequently progress into leukemias, but the factors driving this process are not understood. Here, we find excess Hedgehog (HH) ligand secretion and loss of PTCH2 in myeloproliferative disease, which drives canonical and noncanonical HH-signaling. Interestingly, Ptch2(-/-) mice mimic dual pathway activation and develop a MPN-phenotype with leukocytosis (neutrophils and monocytes), strong progenitor and LKS mobilization, splenomegaly, anemia, and loss of lymphoid lineages. HSCs exhibit increased cell cycling with improved stress hematopoiesis after 5-FU treatment, and this results in HSC exhaustion over time. Cytopenias, LKS loss, and mobilization are all caused by loss of Ptch2 in the niche, whereas hematopoietic loss of Ptch2 drives leukocytosis and promotes LKS maintenance and replating capacity in vitro. Ptch2(-/-) niche cells show hyperactive noncanonical HH signaling, resulting in reduced production of essential HSC regulators (Scf, Cxcl12, and Jag1) and depletion of osteoblasts. Interestingly, Ptch2 loss in either the niche or in hematopoietic cells dramatically accelerated human JAK2V617F-driven pathogenesis, causing transformation of nonlethal chronic MPNs into aggressive lethal leukemias with >30% blasts in the peripheral blood. Our findings suggest HH ligand inhibitors as possible drug candidates that act on hematopoiesis and the niche to prevent transformation of MPNs into leukemias.
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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.