My lab seeks to identify novel tumor suppressor genes involved in the pathogenesis of acute myeloid leukemia (AML) in order to understand how inactivation of these genes cooperates with other genetic events in malignant transformation. A major focus of the lab has been to identify the critical gene(s) lost in AML samples with a deletion of a portion of the long arm of chromosome 9. In about one third to one half of these cases, del(9q) is associated with the common translocation, t(8;21), which creates a chimeric transcription factor called AML1-ETO1. Since AML1-ETO1 alone is apparently insufficient for leukemogenesis, it is likely these two lesions cooperate in leukemogenesis. Using a combination of FISH and loss of heterozygosity (LOH) analyses, we have defined a commonly deleted segment on chromosome 9q of less than 2.1 Mb at 9q21.32. We used a novel in vitro complementation assay to identify two related genes, TLE1 and TLE4, as the most likely candidate tumor suppressor genes from this region. We are now characterizing the role of these proteins in leukemogenesis and normal hematopoiesis using a variety of in vivo and in vitro techniques. We are also characterizing the intracellular signal pathways through which they exert their effects.
We believe that identification and characterization of these genes and other cooperating transforming genes may yield new potential targets for therapy as well as delineate subgroups of patients with differing prognostic features. Identification of cooperating genetic mutations may also allow a more accurate assessment of minimal residual disease in AML during and after treatment and may help identify individuals at high risk of relapse.