UC San Diego

Acute Myeloid Leukemia (AML) is a cancer of the myeloid blood cells. The most common karyotypic abnormality associated with AML is a translocation between chromosomes 8 and 21, resulting in the formation of the AML1-ETO (AE) fusion protein. AE is thought to stimulate leukemogenesis by aberrantly silencing the expression of different genes. Frequently, AE down-regulates genes that are important to normal hematopoiesis, but this fusion protein also silences expression of many other targets unrelated to blood cell differentiation. Using a mouse model of t(8;21) AML, our lab has identified the tumor suppressor, RASSF2, as a gene that is significantly down-regulated in the presence of AE, and has found that this down-regulation may be a critical step in the development of leukemia. Here, we have generated six RASSF2 variants in order to study which structural domains and corresponding functions are the most important to the tumor suppressive function of RASSF2 in t(8;21) AML. We have identified the SARAH domain as the most important for RASSF2 function, and we have found that cytoplasmic localization of RASSF2 may be uniquely important to blood cells. These findings implicate the Hippo pathway as important for repressing leukemogenesis, and also indicate that RASSF2 may play a previously unreported tumor suppressive role in the cytoplasm