Submitted June 21, 2006
Accepted October 16, 2007
FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia
Hyung-Gyoon Kim, Kyoko Kojima, C Scott Swindle, Claudiu V Cotta, Yongliang Huo, Vishnu Reddy, and Christopher A. Klug*
Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL, United States
Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, United States
Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, United States
* Corresponding author; email: chrisk{at}uab.edu.
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 CBF
-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 CBF-SMMHC to promote AML, we co-expressed both mutations in hematopoietic progenitor cells used to reconstitute lethally-irradiated mice. Analysis of transplanted animals showed strong selection for CBF-SMMHC/FLT3-ITD-expressing cells in bone marrow and peripheral blood. Compared to animals transplanted with only CBF-SMMHC-expressing cells, FLT3-ITD further restricted early myeloid differentiation and promoted peripheralization of primitive myeloblasts as early as 2.5 weeks post-transplantation. FLT3-ITD also accelerated disease progression in all CBF-SMMHC/FLT3-ITD-reconstituted animals, which died of a highly aggressive and transplantable AML within 3-5 months. These results indicate that FLT3 activating mutations can cooperate with CBF-SMMHC in an animal model of inv(16)-associated AML.
