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The focus of my laboratory has been to take clinical observations and explore their underlying molecular pathology in a basic research setting, and to take basic research observations or methods and translate these into diagnostic approaches. The major themes of this work have been to investigate the role of chromosomal translocations in the pathogenesis of pediatric malignancies, and to determine how the identification of these genetic lesions can be used to aid in the diagnosis and management of pediatric patients. These efforts are integrated between a clinical molecular diagnostic laboratory and my basic research group. The molecular diagnostic laboratory utilizes a full range of molecular-based methods including TaqMan-based RT-PCR and microchip arrays.
Efforts within my basic research laboratory are focused on the AML1/CBFß transcription factor complex in normal and leukemic hematopoiesis. Our previous work has demonstrated that the AML1/CBFß transcription factor complex, whose genes are the most common target of chromosomal translocations in human leukemia, is essential for the development of definitive fetal liver-derived hematopoiesis. To directly investigate the role of the t(8;21)-encoded AML1-ETO chimeric protein in leukemogenesis, we have recently used gene targeting to create an AML1-ETO knock-in allele. This strategy resulted in the expression of the chimeric gene from the endogenous AML1 regulatory sequences, thus accurately mimicking the t(8;21). Under these conditions, expression of AML1-ETO produced an embryonic lethal phenotype that was almost identical to the one observed after the loss of AML1. This result formally demonstrated that AML1-ETO functions as a dominant inhibitor of normal AML1/CBFß activity. However, although AML1-deficient embryos lacked detectable hematopoietic progenitors, fetal livers from AML1-ETO-expressing embryos contained dysplastic multilineage hematopoietic progenitors that had a high self-renewal capacity and that readily formed immortalized cell lines. These data suggest that AML1-ETO not only represses normal AML1-mediated functions, but also generates signals that contribute to the initiation of aberrant hematopoietic cell proliferation. Importantly, however, AML1-ETO-expressing cells failed to induce leukemia when transplanted into syngeneic or immunocompromised recipients. This latter result suggests that AML1-ETO is insufficient by itself to induce leukemia.
To further define the leukemic potential of AML1-ETO, we have now generated a mouse strain with a conditional germline AML1-ETO allele. These mice contain an AML1-ETO knock-in allele in which a strong transcriptional stop cassette bracketed by LoxP sites was placed 5’ to the AML1-ETO fusion site. As a result, this allele is transcriptionally silent in the germline but can be reactivated after Cre-mediated deletion of the transcriptional stop cassette. These mice are being used to assess the in vivo consequences of AML1-ETO expression and to define the nature of cooperating mutations required to induce a full leukemic phenotype. This murine model should serve as a valuable tool to explore targeted therapy against this molecular subtype of acute leukemia.
Last update: April 2003