Blood online
Home About Blood Authors Subscriptions Permission Advertising Public Access contact us
 

 
Advanced
Current Issue
First Edition
Future Articles
Archives
Submit to Blood
Search
American Society of Hematology
Meeting Abstracts
Email Alerts
 Blood, 5 November 2009, Vol. 114, No. 19, pp. 4186-4196.
Prepublished online as a Blood First Edition Paper on September 8, 2009; DOI 10.1182/blood-2009-05-219550.

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental Tables
Right arrow All Versions of this Article:
blood-2009-05-219550v1
114/19/4186    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Right arrow Rights and Permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Google Scholar
Right arrow Articles by Pellicano, F.
Right arrow Articles by Holyoake, T. L.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pellicano, F.
Right arrow Articles by Holyoake, T. L.
Related Collections
Right arrow Hematopoiesis and Stem Cells
Right arrow Myeloid Neoplasia
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

arrow to previous article Previous Article  |  Table of Contents  |  Next Article next article arrow

MYELOID NEOPLASIA

BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38– cells, through activation of protein kinase Cβ

Francesca Pellicano1, Mhairi Copland1, Heather G. Jorgensen1, Joanne Mountford1, Brian Leber2, and Tessa L. Holyoake1

1 Department of Medicine, Paul O'Gorman Leukaemia Research Centre, Medical Faculty, University of Glasgow, Glasgow, United Kingdom; and 2 Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder maintained by cancer stem cells. To target this population, we investigated the mechanism of action of BMS-214662, developed as a farnesyl transferase inhibitor (FTI) and unique in inducing apoptosis in these cells. By contrast, a related congener and equally effective FTI, BMS-225975 does not induce apoptosis, indicating a novel mechanism of action. BMS-214662 significantly and selectively induced apoptosis in primitive CD34+38– CML compared with normal cells. Apoptosis proceeded via the intrinsic pathway: Bax conformational changes, loss of mitochondrial membrane potential, generation of reactive oxygen species, release of cytochrome c, and caspase-9/3 activation were noted. Up-regulation of protein kinase Cβ (PKCβ), down-regulation of E2F1, and phosphorylation of cyclin A–associated cyclin-dependent kinase 2 preceded these changes. Cotreatment of CML CD34+ and CD34+38– cells with PKC modulators, bryostatin-1, or hispidin markedly decreased these early events and the subsequent apoptosis. None of these events was elicited by BMS-214662 in normal CD34+ cells or by BMS-225975 in CML CD34+ cells. These data suggest that BMS-214662 selectively elicits a latent apoptotic pathway in CML stem cells that is initiated by up-regulation of PKCβ and mediated by Bax activation, providing a molecular framework for development of novel therapeutics.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?




click for free articles
home about blood authors subscriptions permissions advertising public access contact us
  Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020