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: A M S Müller, J Duque, J A Shizuru, M Lübbert
• Journal: Oncogene (Oncogene) Vol. 27 Issue 44 Pg. 5759-73 (Oct 02 2008) ISSN: 1476-5594 [Electronic] England
• PMID: 18604246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Core Binding Factors
• Proto-Oncogene Proteins c-kit

Topics

• Animals
• Chromosome Aberrations
• Core Binding Factors (genetics)
• Disease Models, Animal
• Genetic Complementation Test
• Leukemia, Myeloid, Acute (diagnosis, genetics, pathology)
• Mice
• Mutation
• Prognosis
• Proto-Oncogene Proteins c-kit (genetics)