Overview
Leukemia is the most common cancer seen in childhood. Despite significant progress in the treatment of some pediatric leukemias, the prognosis for a subset of leukemias remains poor. Childhood leukemias that contain the CALM-AF10 fusion protein are especially hard to treat. The presence of CALM-AF10 leads to abnormally high levels of HOXA genes, which are involved in white blood cell development and are known to play a key role in leukemias. However, how CALM-AF10 expression results in elevated HOXA gene expression is unclear. We have previously shown that in order to activate HOXA genes, CALM-AF10 recruits another protein, CRM1, that normally functions to help move other proteins out of the cell nucleus. The involvement of CRM1 in the development of leukemias is novel and unexpected, and our lab is investigating the role of CRM1 in activating HOXA genes and causing leukemia. In particular, we are evaluating novel protein interactions with CRM1 as well as other (non-HOXA) targets of CALM-AF10.
Our current laboratory studies are focused on a novel role for CRM1 in pediatric leukemogenesis – our discovery that CRM1 is directly involved in HOXA gene activation has important implications for leukemias in which HOXA gene expression is increased (CALM-AF10, MLL-, NUP-fusions), and raises the possibility that a novel class of currently available CRM1 inhibitors (Selective Inhibitors of Nuclear Export – SINEs) may function by impairing processes other than just nuclear export. Finally, the investigation of non-HOXA CALM-AF10 target genes may allow for the development of novel approaches to treat these challenging leukemias. Through these approaches, we hope to identify novel therapeutic targets for difficult-to-treat childhood leukemias.