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URL http://www.rockymountainbmt.com/news/A-new-study-quotMultiple-pathways-contribute-to-the-hyperproliferative-responses-from-truncated-granulocyte-colony-stimulating-factor-receptorsquot-is-now-available-10437.html

A new study, "Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors," is now available

03-06-2007

According to recent research from Rotterdam, Netherlands, "Mutations in the granulocyte colony-stimulating factor receptor (G-CSF-R) gene leading to a truncated protein have been identified in a cohort of neutropenia patients highly predisposed to acute myeloid leukemia. Such mutations act in a dominant manner resulting in hyperproliferation but impaired differentiation in response to G-CSF."

"This is due, at least in part, to defective internalization and loss of binding sites for several negative regulators, leading to sustained receptor activation. However, those signaling pathways responsible for mediating the hyperproliferative function have remained unclear. In this study, analysis of an additional G-CSF-R mutant confirmed the importance of residues downstream of Box 2 as important contributors to the sustained proliferation. However, maximal proliferation correlated with the ability to robustly activate signal transducer and activator of transcription (STAT) 5 in a sustained manner, whereas co-expression of dominant-negative STAT5, but not dominant-negative STAT3, was able to inhibit G-CSF-stimulated proliferation from a truncated receptor. Furthermore, a Janus kinase (JAK) inhibitor also strongly reduced the proliferative response, whereas inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) or phosphatidylinositol (PI) 3-kinase reduced proliferation to a lesser degree," wrote J. Gits and colleagues, Erasmus University, Department of Hematology.

The researchers concluded: "These data suggest that sustained JAK2/STAT5 activation is a major contributor to the hyperproliferative function of truncated G-CSF receptors, with pathways involving MEK and PI 3-kinase playing a reduced role."

Gits and colleagues published their study in Leukemia (Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors. Leukemia, 2006;20(12):2111-8).

For additional information, contact J. Gits, Erasmus University Medical Center, Dept. of Hematology, Rotterdam, Netherlands.

This article was prepared by Preventive Medicine Week editors from staff and other reports. Copyright 2007, Preventive Medicine Week via NewsRx.com.