Vorinostat induced cellular stress disrupts the p38 mitogen activated protein kinase and extracellular signal regulated kinase pathways leading to apoptosis in Waldenstrom macroglobulinemia cells

Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Leukemia & lymphoma (Impact Factor: 2.89). 06/2011; 52(9):1777-86. DOI: 10.3109/10428194.2011.577850
Source: PubMed


Histone deacetylases (HDACs) are aberrantly expressed, and inhibitors of HDACs induce apoptosis in lymphoplasmacytic cells (LPCs) in Waldenström macroglobulinemia (WM). The molecular profile by which these agents induce apoptosis in WM LPCs remains to be delineated. We examined the activity of the histone deacetylase inhibitor, vorinostat, and dissected its pro-apoptotic pathways in WM LPCs. Vorinostat induced apoptosis in WM cells through activating specific caspases at varying times. Inhibitors of apoptosis (IAPs) were down-regulated after vorinostat treatment. Cellular stress induced in vorinostat-treated WM cells was reflected by changes in the mitogen activated protein kinase (MAPK) pathways. Activated phospho-p38 MAPK was up-regulated at 12 h, while phospho-extracellular signal-regulated kinase (Erk) abruptly decreased at 24 h. Bortezomib did not augment vorinostat induced primary WM cell killing as reported in other B-cell disorders. These studies support that stress induced apoptosis in vorinostat-treated WM LPCs is mediated through disrupting the activity of the Erk and p38 MAPK pathways.

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Available from: Steven Treon, Jun 05, 2014
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    Leukemia & lymphoma 09/2011; 52(9):1623-5. DOI:10.3109/10428194.2011.573890 · 2.89 Impact Factor
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    ABSTRACT: Waldenström macroglobulinemia (WM) is a distinct hematologic malignancy characterized by a lymphoplasmacytic bone marrow infiltration and the presence of immunoglobulin (Ig)M monoclonal protein. Patients typically present at an advanced age, and a substantial proportion are asymptomatic at diagnosis. A unifying diagnosis of WM may be missed by an unsuspecting hematologist, as symptomatic patients present with a multitude of non-specific manifestations. Although constitutional and neuropathy-related symptoms predominate, concomitant IgM-induced hyperviscosity-associated features can provide useful diagnostic clues. There are specific indications for initiation of therapy. This review focuses on the most up-to-date management strategies of WM, in addition to highlighting the recent discoveries of MYD88 and CXCR4 mutations that have shed unprecedented light on the complex signaling pathways, and opened avenues for novel therapeutic targeting. Although WM remains incurable, with the rapid emergence and integration of effective novel therapies, its clinical course appears poised to improve in the foreseeable future. Copyright © 2015 Elsevier Ltd. All rights reserved.
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