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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4184-4192. Prepublished online as a Blood First Edition Paper on August 28, 2008; DOI 10.1182/blood-2008-02-142190. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-02-142190v1 112/10/4184    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wang, P.-Y. Articles by Jordan, C. T. Search for Related Content PubMed PubMed Citation Articles by Wang, P.-Y. Articles by Jordan, C. T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 26, 2008 Accepted August 8, 2008 The biological properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene Pin-Yi Wang, Fay Young, Chun-Yu Chen, Brett M. Stevens, Sarah J. Neering, Randall M. Rossi, Timothy Bushnell, Igor Kuzin, David Heinrich, Andrea Bottaro, and Craig T. Jordan* Department of Pathology, University of Rochester Medical Center, Rochester, NY, United States Division of Hematology/Oncology, University of Rochester Medical Center, Rochester, NY, United States Department of Chemical Engineering, University of Rochester, Rochester, NY, United States Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, United States James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, United States Department of Medicine, University of Rochester Medical Center, Rochester, NY, United States * Corresponding author; email: craig_jordan{at}urmc.rochester.edu. Recent reports have shown that upon expression of appropriate oncogenes, both stem cells and more differentiated progenitor populations can serve as leukemia-initiating cells. These studies suggest that oncogenic mutations subvert normal development, and induce reacquisition of stem-like features. However, no study has described how specific mutations influence the ability of differentiating cell subsets to serve as leukemia-initiating cells, and if varying such cellular origins confers a functional difference. We have examined the role of the tumor suppressor gene p19ARF in a murine model of acute lymphoblastic leukemia and found that loss of p19ARF changes the spectrum of cells capable of tumor-initiation. With intact p19ARF, only HSC can be directly transformed by BCR/ABL expression. In a p19ARF null genetic background expression of the BCR/ABL fusion protein, renders functionally defined HSC (hematopoietic stem cells), CLP (common lymphoid progenitors), and precursor B-lymphocytes competent to generate leukemia stem cells. Furthermore, we show that leukemias arising from p19ARF null HSC vs. Pro-B cells differ biologically, including relative response to drug insult. Our observations elucidate a unique mechanism by which heterogeneity arises in tumor populations harboring identical genetic lesions and show that activity of p19ARF profoundly influences the nature of tumor-initiating cells during BCR/ABL-mediated leukemogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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