title: Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression.
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.
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany Institute for Molecular Medicine and Cell Research, University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: Claudius
authors.initials: C
authors.lastname: Klein
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
authors.forename: Anabel
authors.initials: A
authors.lastname: Zwick
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kissel
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
authors.forename: Christine Ulrike
authors.initials: CU
authors.lastname: Forster
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Follo
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
authors.forename: Anna Lena
authors.initials: AL
authors.lastname: Illert
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Decker
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Benkler
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Pahl
authors.affiliation: Klinikum rechts der Isar der Technischen Universität München, III. Medizinische Klinik, 81675 München, Germany.
authors.forename: Robert A J
authors.initials: RA
authors.lastname: Oostendorp
authors.affiliation: Department of Pathology, University Medical Center Freiburg, D-79104 Freiburg, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Aumann
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, D-79106 Freiburg, Germany christine.dierks@uniklinik-freiburg.de.
authors.forename: Christine
authors.initials: C
authors.lastname: Dierks
mesh_terms: D000818:Animals; D018450:Disease Progression; D053823:Hedgehog Proteins / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D007938:Leukemia / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008231:Lymphopenia / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D000072079:Patched Receptors; D000072082:Patched-2 Receptor; D010641:Phenotype; D011087:Polycythemia Vera / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D055153:Stem Cell Niche
chemical_list: D053823:Hedgehog Proteins; D008024:Ligands; D050505:Mutant Proteins; C000606238:PTCH2 protein, human; D000072079:Patched Receptors; D000072082:Patched-2 Receptor; C000606241:Ptch2 protein, mouse; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C507924:JAK2 protein, human; D053614:Janus Kinase 2
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