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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5238-5241. Prepublished online as a Blood First Edition Paper on February 22, 2007; DOI 10.1182/blood-2006-09-047050. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-09-047050v1 109/12/5238    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhang, J. Articles by Lodish, H. F. Search for Related Content PubMed PubMed Citation Articles by Zhang, J. Articles by Lodish, H. F. Related Collections Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Brief Report Expression of oncogenic K-ras from its endogenous promoter leads to a partial block of erythroid differentiation and hyperactivation of cytokine-dependent signaling pathways Jing Zhang1, Yangang Liu1, Caroline Beard1, David A. Tuveson2,3, Rudolf Jaenisch1,2, Tyler E. Jacks2, and Harvey F. Lodish1,2 1 Whitehead Institute for Biomedical Research, Cambridge, MA; 2 Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA; 3 Department of Medicine, University of Pennsylvania, Philadelphia, PA When overexpressed in primary erythroid progenitors, oncogenic Ras leads to the constitutive activation of its downstream signaling pathways, severe block of terminal erythroid differentiation, and cytokine-independent growth of primary erythroid progenitors. However, whether high-level expression of oncogenic Ras is required for these phenotypes is unknown. To address this issue, we expressed oncogenic K-ras (K-rasG12D) from its endogenous promoter using a tetracycline-inducible system. We show that endogenous K-rasG12D leads to a partial block of terminal erythroid differentiation in vivo. In contrast to results obtained when oncogenic Ras was overexpressed from retroviral vectors, endogenous levels of K-rasG12D fail to constitutively activate but rather hyperactivate cytokine-dependent signaling pathways, including Stat5, Akt, and p44/42 MAPK, in primary erythroid progenitors. This explains previous observations that hematopoietic progenitors expressing endogenous K-rasG12D display hypersensitivity to cytokine stimulation in various colony assays. Our results support efforts to modulate Ras signaling for treating hematopoietic malignancies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Chan, D. Kalaitzidis, T. Usenko, J. L. Kutok, W. Yang, M. G. Mohi, and B. G. Neel Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis Blood, April 30, 2009; 113(18): 4414 - 4424. [Abstract] [Full Text] [PDF] J. Zhang, J. Wang, Y. Liu, H. Sidik, K. H. Young, H. F. Lodish, and M. D. Fleming Oncogenic Kras-induced leukemogeneis: hematopoietic stem cells as the initial target and lineage-specific progenitors as the potential targets for final leukemic transformation Blood, February 5, 2009; 113(6): 1304 - 1314. [Abstract] [Full Text] [PDF] W.-I. Kim, I. Matise, M. D. Diers, and D. A. Largaespada RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia Blood, January 29, 2009; 113(5): 1086 - 1096. [Abstract] [Full Text] [PDF] T. Kindler, M. G. Cornejo, C. Scholl, J. Liu, D. S. Leeman, J. E. Haydu, S. Frohling, B. H. Lee, and D. G. Gilliland K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to {gamma}-secretase inhibitors Blood, October 15, 2008; 112(8): 3373 - 3382. [Abstract] [Full Text] [PDF] H. Bruchova, M. Merkerova, and J. T. Prchal Aberrant expression of microRNA in polycythemia vera Haematologica, July 1, 2008; 93(7): 1009 - 1016. [Abstract] [Full Text] [PDF]

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