Regulation of Asymmetric Division in Myeloid Leukemogenesis

Early stage myeloid malignancies such as Chronic Myelogenous Leuekemia (CML) and Myelodysplastic syndrome (MDS) are often indolent and slow growing, but can progress with additional mutations to blast crisis CML (bcCML) or AML (Acute Myelogenous Leukemia) which represent an acute aggressive phase marked by the rapid and uncontrolled growth of immature cells. In this more aggressive phase, myeloid leukemias are significantly more resistant to current therapies highlighting the need to better understand the mechanisms that drive their growth and propagation and identify new therapeutic targets. Our previous work has shown that uncontrolled symmetric renewal divisions and concomitant loss of asymmetric division may lead to the establishment and propagation of undifferentiated leukemias. To identify regulators of asymmetric division that may be aberrantly utilized in oncogenic progression, we have focused on the role of the cell fate determinant Staufen 2 (Stau2), a double-stranded RNA binding protein, which has been shown to regulate asymmetric division in Drosophila neuroblasts and mammalian neural stem cells. Our studies using shRNA-mediated knockdown indicate that loss of Stau2 significantly delays the onset of aggressive myeloid disease in vivo and the growth of patient derived myeloid leukemia cells in vitro . Experiments with our newly developed Stau2 genetic loss of function mouse indicate that while loss of Stau2 does not adversely affect normal hematopoiesis, it significantly impairs the propagation of bcCML in vivo by altering the balance between symmetric and asymmetric divisions of the leukemic stem cell populations. Finally, we have carried out a cross-linking immunoprecipitation (CLIP-seq) to identify the downstream targets of Stau2 in myeloid leukemia. Since very little is known about the role of asymmetric division regulators in leukemic progression, these studies collectively define Stau2 as an important new regulator of myeloid malignancies, and provide a basis for determining whether Stau2 inhibition could be an effective strategy in managing clinical disease.