Expression of the TEL-Syk Fusion Protein in Hematopoietic Stem Cells Leads to Rapidly Fatal Myelofibrosis in Mice

被引：9

作者：

Graham, Michelle T. ^{[1
]}

Abram, Clare L. ^{[1
]}

Hu, Yongmei ^{[1
]}

Lowell, Clifford A. ^{[1
]}

机构：

[1] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA

来源：

PLOS ONE | 2013年 / 8卷 / 10期

基金：

美国国家卫生研究院;

关键词：

CHRONIC MYELOID-LEUKEMIA; MYELOPROLIFERATIVE NEOPLASMS; ACTIVATION; MUTATIONS; KINASE; GENE; LEUKEMOGENESIS; PATHOGENESIS; LYMPHOMA; TARGET;

D O I：

10.1371/journal.pone.0077542

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：18