| pubmed-article:15448205 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:15448205 | lifeskim:mentions | umls-concept:C0087111 | lld:lifeskim |
| pubmed-article:15448205 | lifeskim:mentions | umls-concept:C0038250 | lld:lifeskim |
| pubmed-article:15448205 | lifeskim:mentions | umls-concept:C0027022 | lld:lifeskim |
| pubmed-article:15448205 | lifeskim:mentions | umls-concept:C0206454 | lld:lifeskim |
| pubmed-article:15448205 | lifeskim:mentions | umls-concept:C0080347 | lld:lifeskim |
| pubmed-article:15448205 | lifeskim:mentions | umls-concept:C0033681 | lld:lifeskim |
| pubmed-article:15448205 | lifeskim:mentions | umls-concept:C0205177 | lld:lifeskim |
| pubmed-article:15448205 | lifeskim:mentions | umls-concept:C0332466 | lld:lifeskim |
| pubmed-article:15448205 | lifeskim:mentions | umls-concept:C0915830 | lld:lifeskim |
| pubmed-article:15448205 | pubmed:issue | 40 | lld:pubmed |
| pubmed-article:15448205 | pubmed:dateCreated | 2004-10-7 | lld:pubmed |
| pubmed-article:15448205 | pubmed:abstractText | Human stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-fibroblast growth factor receptor (FGFR) 1 fusion tyrosine kinase. Current empirically derived cytotoxic chemotherapy is inadequate for treatment of this disease. We hypothesized that small-molecule inhibitors of the ZNF198-FGFR1 fusion would have therapeutic efficacy. We characterized the transforming activity of ZNF198-FGFR1 in hematopoietic cells in vitro and in vivo. Expression of ZNF198-FGFR1 in primary murine hematopoietic cells caused a myeloproliferative syndrome in mice that recapitulated the human MPD phenotype. Transformation in these assays, and activation of the downstream effector molecules PLC-gamma, STAT5, and phosphatidylinositol 3-kinase/AKT, required the proline-rich domains, but not the ZNF domains, of ZNF198. A small-molecule tyrosine kinase inhibitor, PKC412 (N-benzoyl-staurosporine) effectively inhibited ZNF198-FGFR1 tyrosine kinase activity and activation of downstream effector pathways, and inhibited proliferation of ZNF198-FGFR1 transformed Ba/F3 cells. Furthermore, treatment with PKC412 resulted in statistically significant prolongation of survival in the murine model of ZNF198-FGFR1-induced MPD. Based in part on these data, PKC412 was administered to a patient with t(8;13)(p11;q12) and was efficacious in treatment of progressive myeloproliferative disorder with organomegaly. Therefore, PKC412 may be a useful therapy for treatment of human stem cell leukemia-lymphoma syndrome. | lld:pubmed |
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| pubmed-article:15448205 | pubmed:language | eng | lld:pubmed |
| pubmed-article:15448205 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:15448205 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:15448205 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:15448205 | pubmed:month | Oct | lld:pubmed |
| pubmed-article:15448205 | pubmed:issn | 0027-8424 | lld:pubmed |
| pubmed-article:15448205 | pubmed:author | pubmed-author:MeyerThomasT | lld:pubmed |
| pubmed-article:15448205 | pubmed:author | pubmed-author:ChenJingJ | lld:pubmed |
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| pubmed-article:15448205 | pubmed:author | pubmed-author:XiaoShengS | lld:pubmed |
| pubmed-article:15448205 | pubmed:author | pubmed-author:CohenSarahS | lld:pubmed |
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| pubmed-article:15448205 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:15448205 | pubmed:day | 5 | lld:pubmed |
| pubmed-article:15448205 | pubmed:volume | 101 | lld:pubmed |
| pubmed-article:15448205 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:15448205 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:15448205 | pubmed:pagination | 14479-84 | lld:pubmed |
| pubmed-article:15448205 | pubmed:dateRevised | 2010-5-26 | lld:pubmed |
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