title: Complementing mutations in core binding factor leukemias: from mouse models to clinical applications.
abstract: A great proportion of acute myeloid leukemias (AMLs) display cytogenetic abnormalities including chromosomal aberrations and/or submicroscopic mutations. These abnormalities significantly influence the prognosis of the disease. Hence, a thorough genetic work-up is an essential constituent of standard diagnostic procedures. Core binding factor (CBF) leukemias denote AMLs with chromosomal aberrations disrupting one of the CBF transcription factor genes; the most common examples are translocation t(8;21) and inversion inv(16), which result in the generation of the AML1-ETO and CBFbeta-MYH11 fusion proteins, respectively. However, in murine models, these alterations alone do not suffice to generate full-blown leukemia, but rather, complementary events are required. In fact, a substantial proportion of primary CBF leukemias display additional activating mutations, mostly of the receptor tyrosine kinase (RTK) c-KIT. The awareness of the impact and prognostic relevance of these 'second hits' is increasing with a wider range of mutations tested in clinical trials. Furthermore, novel agents targeting RTKs are emanating rapidly and entering therapeutic regimens. Here, we present a concise review on complementing mutations in CBF leukemias including pathophysiology, mouse models, and clinical implications.
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Baden Wuerttemberg, Freiburg, Germany.
authors.forename: A M S
authors.initials: AM
authors.lastname: Müller
authors.forename: J
authors.initials: J
authors.lastname: Duque
authors.forename: J A
authors.initials: JA
authors.lastname: Shizuru
authors.forename: M
authors.initials: M
authors.lastname: Lübbert
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations; D050660:Core Binding Factors / Q000235:genetics*; D004195:Disease Models, Animal; D005816:Genetic Complementation Test; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*
chemical_list: D050660:Core Binding Factors; D019009:Proto-Oncogene Proteins c-kit