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Perspectives
Pathophysiology Defined by Altered Signal Transduction Pathways: The Role of JAK-STAT and PI3K Signaling in Leukemic Large Granular Lymphocytes
Andrew E. Schade, Marcin W. Wlodarski and Jaroslaw P. Maciejewski
volume 5 | issue 22
15 november 2006Pages: 2571 - 2574
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Signal transduction pathways integrate a variety of microenvironmental cues to guide cell function by regulating gene transcription, cell cycle status, growth, and differentiation. It is well established that perturbation of these processes plays a key role in hematologic malignancies including lymphomas and chronic and acute lymphocytic leukemias. Altered intracellular signaling pathways have been proposed to mediate many biological properties of T cell large granular lymphocytic leukemia (T-LGL), a disorder characterized by a clonal proliferation of CD8 T cells resulting in immune-mediated cytopenias, most commonly neutropenia. Since T-LGL offers a unique opportunity to study signal transduction in the pathologic clonal cytotoxic T cell (CTL) compared to normal CTL, we have investigated a potential imbalance in T-LGL pro-survival signaling to define the mechanisms underlying the semi-autonomous proliferation leading to leukemia. Increased activity of the PI3K-AKT signaling axis in T-LGL cells appears to operate in conjunction with or parallel to increased STAT3 activation in these cells to inhibit the apoptotic program. This contrasts with recently reported findings in which STAT3 was shown to induce apoptosis in mammary gland epithelial cells via inhibition of the PI3K-AKT pathway, highlighting how signaling pathways interact to direct effector function in a cell-specific manner. Furthermore, the ability to define pathophysiology at the molecular level opens new avenues for targeted therapeutics.
Authors
Andrew E. Schade
Cleveland Clinic, Cleveland OH
Marcin W. Wlodarski
Cleveland Clinic, Cleveland OH
Jaroslaw P. Maciejewski
Cleveland Clinic, Cleveland OH
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.