Molecular basis for leukemic transformation caused by chimeric protein involving the transcription factor AML1 (PEBP2aB).

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AML1 (PEBP2αB) encodes the DNA-binding subuit for the hematopoiesis-related transcription factor complex, PEBP2 (CBF), which is the most frequent target of the human leukemia-associated gene aberrations. We investigated the molecular mechanism of actions played by AML1 and how its mutations contribute to the development of leukemia, by using gene-targeting experiments. Our results are summarized as follows :1. We established that the biologic activity of AML1 to support the development of definitive hematopoiesis depends on its trans-activating activity and that its most C-terminal trans-repression domain is dispensable for this action by in vivo hematopoietic rescue experiments.2. We newly cloned the CDNA encoding the AML1c isoform, which is differentially expressed under the control of the distal promoter of AML1 gene locus, in contrast to AML1b isoform, whose expression is regulated by the proximal promoter. While AML1b was expressed ubiquitously, the expression of AML1c appeared to be more closely related to the definitive hematopoiesis and is dependent on the presence of active AML1 gene locus.3. We analyzed the fate of the mouse embryonic stem cell clones which carry a knocked-in AML1-MTG8 leukemic gene within the chimeric mice, and found that the knock-in clones could contribute to the hematopoietic tissues of adult mice. However, they never developed overt leukemia so far as they were kept in the specific-pathogen free atmosphere, indicating that this chimeric leukemia gene is necessary but not sufficient for the leukemogenesis.We are currently generating the germline knock-in mice which carry leukemia associated point mutation(s) of AML1 gene to further define how this gene-mutation contribute to the leukemogenesis.