title: FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia.
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 CBFbeta-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 CBFbeta-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 CBFbeta-SMMHC/FLT3-ITD-expressing cells in bone marrow and peripheral blood. Compared with animals transplanted with only CBFbeta-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 CBFbeta-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 CBFbeta-SMMHC in an animal model of inv(16)-associated AML.
authors.affiliation: Department of Microbiology, Division of Developmental and Clinical Immunology, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.
authors.forename: Hyung-Gyoon
authors.initials: HG
authors.lastname: Kim
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kojima
authors.forename: C Scott
authors.initials: CS
authors.lastname: Swindle
authors.forename: Claudiu V
authors.initials: CV
authors.lastname: Cotta
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Huo
authors.forename: Vishnu
authors.initials: V
authors.lastname: Reddy
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klug
mesh_terms: D000818:Animals; D007446:Chromosome Inversion / Q000235:genetics*; D050658:Core Binding Factor beta Subunit / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D038041:Lymphopoiesis; D051379:Mice; D009154:Mutation / Q000235:genetics; D038042:Myelopoiesis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D024745:Smooth Muscle Myosins / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050658:Core Binding Factor beta Subunit; D015514:Oncogene Proteins, Fusion; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; D024745:Smooth Muscle Myosins