Current Research and Scholarly Interests
Transcriptional regulation in leukemogenesis
CREB is a leucine zipper transcription factor that controls cell proliferation, differentiation, and survival. CREB is overexpressed in bone marrow cells from the majority of patients with acute lymphoblastic and myeloid leukemia. CREB transgenic mice develop myeloproliferative disease, i.e. preleukemia, but not acute leukemia. Therefore, CREB is an oncogene that requires additional mutations. We are studying other cooperating oncogenes that contribute to leukemogenesis. In addition, downstream target genes are being explored. We are also studying a small molecule inhibitor of CREB for the treatment of acute leukemia.
Targeted therapy for leukemia and other cancers
In collaboration with pharmaceutical companies, we are testing novel compounds to target specific signaling molecules in AML. Among the small molecules being studied in vitro and in vivo are inhibitors of receptor tyrosine kinases, aurora kinases, and anti-apoptotic proteins. Mechanistic pathways are being investigated.
Protacs are chimeric molecules to target cancer causing proteins for ubiquitination and degradation. We have demonstrated the feasibility of using this approach in prostate and breast cancer cell lines to target the androgen and estrogen receptors for ubiquitination and degradation, resulting in apoptosis. Approaches are being developed to design Protacs for clinical trials in humans.
Signaling Pathways in bone marrow failure syndromes
Defects in ribosome biogenesis have been associated with specific bone marrow failure syndromes, such as Diamond Blackfan Anemia. We are studying the signaling pathways that are altered by deficiency in specific ribosomal protein subunits. Zebrafish, mouse, and human cells are being used to characterize p53-dependent and –independent pathways mediating aberrant erythropoiesis and increased risk of cancer in these patients. Novel drugs are being tested.