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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3849-3858. Prepublished online as a Blood First Edition Paper on February 1, 2008; DOI 10.1182/blood-2007-08-109942. This Article Full Text Full Text (PDF) Supplemental Appendix All Versions of this Article: blood-2007-08-109942v1 111/7/3849    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 Li, L. Articles by Small, D. Search for Related Content PubMed PubMed Citation Articles by Li, L. Articles by Small, D. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model Li Li1, Obdulio Piloto1, Ho Bao Nguyen1, Kathleen Greenberg1, Kogo Takamiya2, Frederick Racke3, David Huso1,4, and Donald Small1,5 1 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology; Departments of2 Neurological Surgery; 3 Pathology; 4 Molecular and Comparative Pathobiology; and 5 Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD Constitutive activation of FMS-like tyrosine kinase 3 (FLT3) by internal tandem duplication (ITD) mutations is one of the most common molecular alterations known in acute myeloid leukemia (AML). To investigate the role FLT3/ITD mutations play in the development of leukemia, we generated a FLT3/ITD knock-in mouse model by inserting an ITD mutation into the juxtamembrane domain of murine Flt3. FLT3wt/ITD mice developed myeloproliferative disease, characterized by splenomegaly, leukocytosis, and myeloid hypercellularity, which progressed to mortality by 6 to 20 months. Bone marrow (BM) and spleen from FLT3wt/ITD mice had an increased fraction of granulocytes/monocytes and dendritic cells, and a decreased fraction of B-lymphocytes. No sign of acute leukemia was observed over the lifetime of these mice. BM from FLT3wt/ITD mice showed enhanced potential to generate myeloid colonies in vitro. BM from FLT3wt/ITD mice also produced more spleen colonies in the in vivo colony-forming unit (CFU)–spleen assay. In the long-term competitive repopulation assay, BM cells from FLT3wt/ITD mice outgrew the wild-type competitor cells and showed increased myeloid and reduced lymphoid expansion activity. In summary, our data indicate that expression of FLT3/ITD mutations alone is capable of conferring normal hematopoietic stem/progenitor cells (HSPCs) with enhanced myeloid expansion. It also appears to suppress B lymphoid maturation. Additional cooperative events appear to be required to progress to acute leukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Fukuda, P. Singh, A. Moh, M. Abe, E. M. Conway, H. S. Boswell, S. Yamaguchi, X.-Y. Fu, and L. M. Pelus Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3 Blood, July 9, 2009; 114(2): 394 - 403. [Abstract] [Full Text] [PDF]

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