NDLI: FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia

Content Provider	PubMed Central
Author	Kim, Hyung-gyoon Kojima, Kyoko Swindle, C. Scott Cotta, Claudiu V. Huo, Yongliang Reddy, Vishnu Klug, Christopher A.
Copyright Year	2008
Abstract	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.
Related Links	http://dx.doi.org/10.1182/blood-2006-06-030312
Starting Page	1567
File Format	PDF
ISSN	15280020
e-ISSN	15280020
Journal	Blood
Issue Number	3
Volume Number	111
Language	English
Publisher	American Society of Hematology
Publisher Date	2008-02-01
Access Restriction	Open
Rights Holder	American Society of Hematology
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Hematology Biochemistry Immunology

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