| Title |
Expression of the TEL-Syk Fusion Protein in Hematopoietic Stem Cells Leads to Rapidly Fatal Myelofibrosis in Mice
|
|---|---|
| Published in |
PLOS ONE, October 2013
|
| DOI | 10.1371/journal.pone.0077542 |
| Pubmed ID | |
| Authors |
Michelle T. Graham, Clare L. Abram, Yongmei Hu, Clifford A. Lowell |
| 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. |
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| Country | Count | As % |
|---|---|---|
| Hungary | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
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| Country | Count | As % |
|---|---|---|
| Unknown | 20 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 6 | 30% |
| Student > Ph. D. Student | 4 | 20% |
| Student > Bachelor | 2 | 10% |
| Professor | 2 | 10% |
| Student > Doctoral Student | 1 | 5% |
| Other | 4 | 20% |
| Unknown | 1 | 5% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 6 | 30% |
| Medicine and Dentistry | 4 | 20% |
| Agricultural and Biological Sciences | 3 | 15% |
| Pharmacology, Toxicology and Pharmaceutical Science | 1 | 5% |
| Immunology and Microbiology | 1 | 5% |
| Other | 3 | 15% |
| Unknown | 2 | 10% |