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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1567-1574. Prepublished online as a Blood First Edition Paper on October 29, 2007; DOI 10.1182/blood-2006-06-030312. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-06-030312v1 111/3/1567    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 Kim, H.-G. Articles by Klug, C. A. Search for Related Content PubMed PubMed Citation Articles by Kim, H.-G. Articles by Klug, C. A. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia Hyung-Gyoon Kim1, Kyoko Kojima1, C. Scott Swindle1, Claudiu V. Cotta2, Yongliang Huo3, Vishnu Reddy2, and Christopher A. Klug13 Departments of1 Microbiology, 2 Pathology, and 3 Biochemistry and Molecular Genetics, Division of Developmental and Clinical Immunology, University of Alabama at Birmingham The inversion of chromosome 16 in the inv(16)(p13q22) is one of the most frequent cytogenetic abnormalities observed in acute myeloid leukemia (AML). The inv(16) fuses the core binding factor (CBF) beta subunit with the coiled-coil rod domain of smooth muscle myosin heavy chain (SMMHC). Expression of CBFβ-SMMHC in mice does not promote AML in the absence of secondary mutations. Patient samples with the inv(16) also possess mutually exclusive activating mutations in either N-RAS, K-RAS, or the receptor tyrosine kinases, c-KIT and FLT3, in almost 70% of cases. To test whether an activating mutation of FLT3 (FLT3-ITD) would cooperate with CBFβ-SMMHC to promote AML, we coexpressed both mutations in hematopoietic progenitor cells used to reconstitute lethally irradiated mice. Analysis of transplanted animals showed strong selection for CBFβ-SMMHC/FLT3-ITD–expressing cells in bone marrow and peripheral blood. Compared with animals transplanted with only CBFβ-SMMHC–expressing cells, FLT3-ITD further restricted early myeloid differentiation and promoted peripheralization of primitive myeloblasts as early as 2.5 weeks after transplantation. FLT3-ITD also accelerated disease progression in all CBFβ-SMMHC/FLT3-ITD–reconstituted animals, which died of a highly aggressive and transplantable AML within 3 to 5 months. These results indicate that FLT3-activating mutations can cooperate with CBFβ-SMMHC in an animal model of inv(16)-associated AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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