Rescue of a primary myelofibrosis model by retinoid-antagonist therapy

Suk Hyun Hong, Melita Dvorak-Ewell, Hazel Y. Stevens, Grant D. Barish, Glenda L. Castro, Russell Nofsinger, John A. Frangos, Dolores Shoback, Ronald M. Evans*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRTmRID) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRTmRID 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 SMRTmRID mice results in up-regulation of TGF-? 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.

Original languageEnglish (US)
Pages (from-to)18820-18825
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number47
DOIs
StatePublished - Nov 19 2013

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Rescue of a primary myelofibrosis model by retinoid-antagonist therapy'. Together they form a unique fingerprint.

Cite this