{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:57:50Z","timestamp":1791075470787,"version":"4.1.0"},"reference-count":45,"publisher":"National Academy of Sciences","issue":"41","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,10,9]]},"abstract":"<jats:p>Deregulation of microRNA (miRNA) expression can lead to cancer initiation and progression. However, limited information exists on the function of miRNAs in cancer maintenance. We examined these issues in the case of myeloproliferative diseases and neoplasms (MPN), a collection of hematopoietic neoplasms regarded as preleukemic, thereby representing early neoplastic states. We report here that microRNA-125a (miR-125a)\u2013induced MPN display a complex manner of oncogene dependence. Following a gain-of-function genomics screen, we overexpressed candidate miR-125a in vivo, which led to phenotypes consistent with an atypical MPN characterized by leukocytosis, monocytosis, splenomegaly, and progressive anemia. The diseased MPN state could be recapitulated in a doxycycline-inducible mouse model. Upon doxycycline withdrawal, the primary MPN phenotypes rapidly resolved after the discontinuation of miR-125a overexpression. However, reinduction of miR-125a led to complex phenotypes, with some animals rapidly developing lethal anemia with extensive damages in the spleen. Forced expression of miR-125a resulted in elevated cellular tyrosine phosphorylation and hypersensitivity toward hematopoietic cytokines. Furthermore, we demonstrate that miR-125a targets multiple protein phosphatases. Our data demonstrate that miR-125a\u2013induced MPN is addicted to its sustained overexpression, and highlight the complex nature of oncogenic miRNA dependence in an early neoplastic state.<\/jats:p>","DOI":"10.1073\/pnas.1213196109","type":"journal-article","created":{"date-parts":[[2012,9,25]],"date-time":"2012-09-25T06:48:49Z","timestamp":1348555729000},"page":"16636-16641","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":42,"title":["Complex oncogene dependence in microRNA-125a\u2013induced myeloproliferative neoplasms"],"prefix":"10.1073","volume":"109","author":[{"given":"Shangqin","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Genetics,"},{"name":"Yale Stem Cell Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Genetics,"},{"name":"Department of Hematology, Shanghai First People's Hospital Shanghai 200080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia M.","family":"Megyola","sequence":"additional","affiliation":[{"name":"Department of Genetics,"},{"name":"Yale Stem Cell Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Halene","sequence":"additional","affiliation":[{"name":"Department of Medicine,"},{"name":"Yale Stem Cell Center, and"},{"name":"Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane S.","family":"Krause","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine,"},{"name":"Yale Stem Cell Center, and"},{"name":"Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T.","family":"Scadden","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Massachusetts General Hospital, Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Boston, MA 02114; 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