SEARCH:   Advanced

Blood, 5 February 2009, Vol. 113, No. 6, pp. 1304-1314. Prepublished online as a Blood First Edition Paper on December 9, 2008; DOI 10.1182/blood-2008-01-134262. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2008-01-134262v1 113/6/1304    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Zhang, J. Articles by Fleming, M. D. Search for Related Content PubMed PubMed Citation Articles by Zhang, J. Articles by Fleming, M. D. Related Collections Hematopoiesis and Stem Cells Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Oncogenic Kras-induced leukemogeneis: hematopoietic stem cells as the initial target and lineage-specific progenitors as the potential targets for final leukemic transformation Jing Zhang1,2, Jing Wang1, Yangang Liu1,2, Harwin Sidik3, Ken H. Young4, Harvey F. Lodish1,5, and Mark D. Fleming6 1 Whitehead Institute for Biomedical Research, Cambridge, MA; 2 McArdle Laboratory for Cancer Research and 3 Department of Molecular Biology, University of Wisconsin, Madison; 4 Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Paul P. Carbone Comprehensive Cancer Center, Madison; 5 Department of Biology, Massachusetts Institute of Technology, Cambridge; and 6 Department of Pathology, Children's Hospital Boston, MA KRAS is often mutated in human hematopoietic malignancies, including juvenile myelomonocytic leukemia (JMML) and T-cell lymphoblastic leukemia/lymphoma (TLL/L). However, the exact role and function of oncogenic KRAS mutations in the initiation and progression of JMML and TLL/L remain elusive. Here, we report the use of a mouse bone marrow transplantation model to study oncogenic Kras-induced leukemogenesis. We show that as the first genetic hit, oncogenic Kras mutations initiate both JMML and TLL/L, but with different efficiencies. Limiting dilution analyses indicated that an oncogenic Kras mutation alone is insufficient to produce frank malignancy. Instead, it cooperates with additional subsequent genetic event(s). Moreover, transplantation of highly purified hematopoietic stem cells (HSCs) and myeloid progenitors identified HSCs as the primary target for the oncogenic Kras mutation. Karyotypic analysis further indicated that secondary genetic hit(s) target lineage-specific progenitors rather than HSCs for terminal tumor transformation into leukemic stem cells. Thus, we propose the cellular mechanism underlying oncogenic Kras-induced leukemogenesis, with HSCs as the primary target by the oncogenic Kras mutations and lineage-committed progenitors as the final target for cancer stem cell transformation. Our model might be also applicable to other solid tumors harboring oncogenic Kras mutations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020