Mentor Name: Daniel Wechsler

We have recently described the role of the homeobox gene SIX1 in leukemias, involving demonstration of efficacy of an EYA2 inhibitor in SIX1-expressing leukemias in vitro and in vivo, including murine PICALM MLLT10 leukemia and human Jurkat and SHI-1 leukemias. Additionally, previous work has shown the importance of XPO1 and Menin in MLLT10 fusion leukemias. As a corollary to this work, we have started to evaluate the effect of combining the EYA2 inhibitor LG1-34 with an XPO1 inhibitor (KPT-330), given the critical nature of XPO1 in PICALM-MLLT10 leukemia. Unpublished work from our lab has shown that the PICALM MLLT10 oncogene interacts with menin. Based on these findings, we propose to study the effect of small molecule inhibitors of EYA2 (LG1-34), XPO1 (KPT-330), and Menin (SNDX-5613) in PICALM MLLT10 and other SIX1-expressing leukemias. We will be assessing the effect on proliferation and apoptosis of these inhibitors alone and, more importantly, in combination to evaluate if the agents synergize.