title: Rescue of a primary myelofibrosis model by retinoid-antagonist therapy.
abstract: Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRT(mRID)) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRT(mRID) mice develop spontaneous primary myelofibrosis, a chronic, usually idiopathic disorder characterized by progressive bone marrow fibrosis. Frequently linked to polycythemia vera and chronic myeloid leukemia, myelofibrosis displays high patient morbidity and mortality, and current treatment is mostly palliative. To decipher the etiology of this disease, we identified the thrombopoietin (Tpo) gene as a target of the SMRT-retinoic acid receptor signaling pathway in bone marrow stromal cells. Chronic induction of Tpo in SMRT(mRID) mice results in up-regulation of TGF-β and PDGF in megakaryocytes, uncontrolled proliferation of bone marrow reticular cells, and fibrosis of the marrow compartment. Of therapeutic relevance, we show that this syndrome can be rescued by retinoid antagonists, demonstrating that the physical interface between SMRT and retinoic acid receptor can be a potential therapeutic target to block primary myelofibrosis disease progression.
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Suk-Hyun
authors.initials: SH
authors.lastname: Hong
authors.forename: Melita
authors.initials: M
authors.lastname: Dvorak-Ewell
authors.forename: Hazel Y
authors.initials: HY
authors.lastname: Stevens
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barish
authors.forename: Glenda L
authors.initials: GL
authors.lastname: Castro
authors.forename: Russell
authors.initials: R
authors.lastname: Nofsinger
authors.forename: John A
authors.initials: JA
authors.lastname: Frangos
authors.forename: Dolores
authors.initials: D
authors.lastname: Shoback
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D052160:Benzothiazoles; D001853:Bone Marrow / Q000378:metabolism*; D002118:Calcium / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D003959:Diamines; D004797:Enzyme-Linked Immunosorbent Assay; D063185:Epigenetic Repression / Q000502:physiology*; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D008156:Luciferases; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D056985:Nuclear Receptor Co-Repressor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D009930:Organic Chemicals; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D016133:Polymerase Chain Reaction; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000209:etiology; D011804:Quinolines; D015398:Signal Transduction / Q000502:physiology*; D013926:Thrombopoietin / Q000096:biosynthesis / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D016207:Cytokines; D017931:DNA Primers; D003959:Diamines; D056985:Nuclear Receptor Co-Repressor 2; D009930:Organic Chemicals; D010982:Platelet-Derived Growth Factor; D011804:Quinolines; D016212:Transforming Growth Factor beta; C075278:platelet-derived growth factor A; C098022:SYBR Green I; D013926:Thrombopoietin; D008156:Luciferases; D000469:Alkaline Phosphatase; D002118:Calcium
keywords: myelodysplastic syndrome; ostesclerosis; splenomegaly