Project Abstract This proposal describes a research plan and a training program to facilitate Dr. Gondek’s transition from a junior faculty member to an independent investigator. Dr. Gondek studied the genetics of Bone Marrow Failure Syndromes and in particular Myelodysplastic Syndromes (MDS) in the laboratory of Dr. Jaroslaw Maciejewski at Cleveland Clinic. As a hematology fellow in the laboratory of Dr. William Matsui at The Johns Hopkins University, Dr. Gondek studied the role of Hedgehog (Hh) signaling in the development and progression of hematologic malignancies. Dr. Matsui, Dr. Gondek’s primary mentor, is a world-renowned expert in the field and was the first to report the importance Hedgehog signaling in the regulation of cancer stem cells in multiple myeloma and pancreatic cancer. Upon completion of his clinical and research fellowship Dr. Gondek joined the faculty as an Instructor of Oncology to develop the research translational program in MDS. Support from the K08 Career Development Award will enable Dr. Gondek to gain additional skills, receive mentorship and protected time to advance his academic career. Dr. Gondek’s goal is to become an independent investigator in and leader in MDS translational research. In this application Dr. Gondek will study the role of a key regulator of Hedgehog signaling, Gli2, in normal hematopoiesis and progression of MDS. Hedgehog signaling seems to be a promising target in human malignancies and its inhibition has shown to be effective in certain tumors. To this end, the efforts to explain the role of Hh in normal and malignant hematopoiesis focused on upstream components of the pathway (e.g. Patched and Smoothened) but the results have been ambiguous. In this proposal Dr. Gondek will elucidate the function of the key Hh regulator Gli2 in normal and malignant hematopoiesis and define the role Gli2 as a selective and safe therapeutic target. Using transgenic animal models the proposed research will elucidate the role of Gli2 loss and gain-of- function in normal hematopoiesis and MDS progression. These goals will be achieved through the following aims: 1) Determine the role of Gli2 loss in (a) normal definitive hematopoiesis and (b) MDS progression using Nup98-HoxD13 mouse model, 2) Determine the requirements of Gli2 activator for (a) normal hematopoiesis and its role in (b) progression of MDS. Results of this research will further the understanding of Gli2 function in normal and malignant hematopoiesis. The investigators hypothesize that this project will provide novel insights into the processes that drive MDS progression and may lead to strategies focused on targeted Gli2 inhibition as a new treatment for high risk MDS and leukemia.