Abstract Abstract 1221 Constitutive activation of the FGFR1 kinase domain through rearrangement with dimerization domains from various proteins leads to an atypical myeloproliferative disease (MPD). Although the majority of these rearrangements result in development of T-cell leukemia/lymphoma, in the case of the BCR-FGFR1 rearrangement the phenotype is predominantly a myeloid and B cell MPD. To investigate the etiology of this disease, a murine model of BCR-FGFR1 was created using a bone marrow transduction/transplantation approach. Consistent with the human disease, recipient mice developed clear myeloproliferations marked by CML-like basophilia as well as extramedullary leukemic transformation containing myelo- or lymphoblasts, with neoplasms of myeloid and B cell lineages. Flow analysis demonstrated a CD43+ phenotype in leukemic B cells suggesting a block in the differentiation of pro-B progenitor cells. A cell line (BBC1) has now been established with this immature B cell immunophenotype albeit B220-, consistent with a recently described B1 progenitor. These cells can differentiate in vitro with characteristics of both macrophage and dendritic lineages. When BBC1 cells are injected into normal mice, leukemogenesis marked by a hypercellular bone marrow and splenomegaly is induced. Although BBC cells show the same progenitor B cell immunophenotype seen in the parent cells throughout the hematopoietic system, tumor cells in the peritoneum lose CD43 expression, down-regulate CD19 expression and upregulate CD11b and F4/80 demonstrating a capacity to differentiate in this environment. In this model, therefore, the etiology of BCR-FGFR1 disease closely mimics that seen in humans and we have identified a likely B cell subtype involved in leukemic transformation. Disclosures: No relevant conflicts of interest to declare.