Human stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and͞or 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-␥, STAT5, and phosphatidylinositol 3-kinase͞AKT, 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 Ba͞F3 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. R ecurrent translocations involving the region p11-p12 of chromosome 8 have been associated with two distinct clinical hematopoietic malignancies: acute myeloid leukemia (AML) or stem cell myeloproliferative disorder (MPD). Patients with MPD are characterized by myeloid hyperplasia with peripheral blood eosinophilia and B or T cell lymphoma. As we and others reported, the myeloid hyperplasia generally progresses to acute myeloid leukemia within a year of the original diagnosis, and a cure requires allogeneic stem cell transplantation (1, 2).Positional cloning of recurrent chromosomal translocations associated with the MPD has demonstrated frequent involvement of the FGFR1 gene on 8p11.2-11.1, encoding a receptor tyrosine kinase that is normally activated by fibroblast growth factors. To date, four different translocations have been described, including t(8;13)(p11;q12), t(8;9)(p11;q33), t(6;8)(q27;p11), and t(8;22)(p11;q11), which result in fusion of distinct partners to fibroblast growth factor receptor (FGFR) 1, including ZNF198 (3), CEP110 (4), FOP (5), and BCR (6), respectively. In each case, an N-terminal partner containing self-association motif is fused to the C-terminal tyrosine kinase domain of FGFR1. Recently, a fifth translocation, t(8;19)(p12;q13.3), associated with this syndrome has been cloned, and it results in an N-terminal portion of the human endogenous...