title: Expression of the TEL-Syk fusion protein in hematopoietic stem cells leads to rapidly fatal myelofibrosis in mice.
abstract: The TEL-Syk fusion protein was isolated from a patient with myelodysplasia with megakaryocyte blasts. Expression of TEL-Syk transforms interleukin-3 (IL-3)-dependent Ba/F3 cells in vitro by deregulating STAT5-mediated signal transduction pathways. In vivo, TEL-Syk expression in pre-B cells blocks B cell differentiation, leading to lymphoid leukemia. Here, we demonstrate that TEL-Syk introduced into fetal liver hematopoietic cells, which are then adoptively transferred into lethally irradiated recipients, leads to an aggressive myelodysplasia with myelofibrosis that is lethal in mice by 60-75 days. Expression of TEL-Syk induces a short-lived myeloexpansion that is rapidly followed by bone marrow failure and extreme splenic/hepatic fibrosis accompanied by extensive apoptosis. The disease is dependent on Syk kinase activity. Analysis of serum from TEL-Syk mice reveals an inflammatory cytokine signature reminiscent of that found in the sera from patients and mouse models of myeloproliferative neoplasms. TEL-Syk expressing cells showed constitutive STAT5 phosphorylation, which was resistant to JAK inhibition, consistent with deregulated cytokine signaling. These data indicate that expression of TEL-Syk in fetal liver hematopoietic cells results in JAK-independent STAT5 phosphorylation ultimately leading to a uniquely aggressive and lethal form of myelofibrosis.
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Graham
authors.forename: Clare L
authors.initials: CL
authors.lastname: Abram
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Hu
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
mesh_terms: D000740:Anemia / Q000235:genetics; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D049109:Cell Proliferation; D002678:Chimera; D015870:Gene Expression; D057809:HEK293 Cells; D006411:Hematopoiesis, Extramedullary; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010766:Phosphorylation; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000473:pathology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013163:Splenomegaly / Q000235:genetics; D013921:Thrombocytopenia / Q000235:genetics
chemical_list: D015514:Oncogene Proteins, Fusion; D050799:STAT5 Transcription Factor; C000588904:TEL-Syk fusion protein, human