{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T20:11:51Z","timestamp":1792872711009,"version":"4.5.0"},"reference-count":43,"publisher":"American Society of Hematology","issue":"19","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,11,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>High levels of expression of wild-type Flt3 characterize many hematopoietic proliferative diseases and neoplasms, providing a potential therapeutic target. Using the c-Cbl RING finger mutant mouse as a model of a myeloproliferative disease (MPD) driven by wild-type Flt3, in the present study, we show that treatment with the Flt3 kinase inhibitor AC220 blocks MPD development by targeting Flt3+ multipotent progenitors (MPPs). We found that daily administration of AC220 caused a marked reduction in Flt3 expression, induction of quiescence, and a significant loss of MPPs within 4 days. Unexpectedly, a robust Flt3 ligand\u2013associated proliferative recovery response soon followed, preventing further loss of MPPs. However, continued AC220 treatment limited MPP recovery and maintained reduced, steady-state levels of cycling MPPs that express low levels of Flt3. Therefore, a finely tuned balance between the opposing forces of AC220 and Flt3 ligand production was established; whereas the Flt3 ligand blunted the inhibitory effects of AC220, the disease was held in remission for as long as therapy was continued. The net effect is a potent therapy indicating that patients with c-Cbl mutations, or those with similarly enhanced Flt3 signaling, may respond well to AC220 even after the induction of high levels of Flt3 ligand.<\/jats:p>","DOI":"10.1182\/blood-2012-06-436675","type":"journal-article","created":{"date-parts":[[2012,9,18]],"date-time":"2012-09-18T23:11:28Z","timestamp":1348009888000},"page":"4049-4057","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":39,"title":["Flt3 inhibitor AC220 is a potent therapy in a mouse model of myeloproliferative disease driven by enhanced wild-type Flt3 signaling"],"prefix":"10.1182","volume":"120","author":[{"given":"Samuel J.","family":"Taylor","sequence":"first","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Australia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha A.","family":"Dagger","sequence":"additional","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Australia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine B. F.","family":"Thien","sequence":"additional","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Australia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew E.","family":"Wikstrom","sequence":"additional","affiliation":[{"name":"Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wallace Y.","family":"Langdon","sequence":"additional","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Australia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"5","key":"2019111808190581800_B1","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1182\/blood-2002-02-0492","article-title":"The roles of FLT3 in hematopoiesis and leukemia.","volume":"100","author":"Gilliland","year":"2002","journal-title":"Blood"},{"issue":"2","key":"2019111808190581800_B2","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S1535-6108(03)00003-5","article-title":"Inhibition of FLT3 in MLL. 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