Daniel G. Tenen

Dr. Tenen's laboratory focuses on transcription factors and gene regulation, and their relationship to differentiation. The laboratory has characterized transcription factors which play a role in the differentiation of hematopoietic stem cells into different specific lineages, with particular focus on myeloid (granulocyte and monocyte) differentiation in normal and leukemic cells. The laboratory has isolated and characterized regulatory elements of genes which are expressed at different stages of myeloid differentiation, including CD34, a stem cell specific gene expressed only in the earliest hematopoietic progenitors, as well as two master transcription factors which are regulators of myeloid development: the Ets factor PU.1, and C/EBP alpha. Our studies have demonstrated a role for PU.1 and C/EBP alpha in the myeloid specific expression of a number of important myeloid genes, including the three myeloid CSF (GM, M, and G) receptors, and expression and knockout studies of PU.1 and C/EBP alpha show they play a major role in development of specific myeloid lineages. Current efforts in the laboratory focus on understanding regulation, signal transduction pathways, and interacting partners of PU.1 and C/EBP alpha, and their role in stem cells. We have now identified mutations and specific abnormalities in expression and function of C/EBP alpha and PU.1 in specific subtypes of myeloid leukemias, and a major effort in our laboratory is now focused on further characterization of the role of C/EBP alpha and PU.1 in leukemogenesis, as well as developing drugs and other therapies specifically aimed at C/EBP alpha and PU.1. We are also studying conditional knockouts of PU.1 and C/EBP alpha to study their function in the adult animal, as well as knock-downs resulting from targeted disruption of their regulatory regions. Other projects directed at leukemogenic mechanisms include models of murine leukemia using inducible expression of translocation fusion proteins, such as the Bcr-Abl protein. Our long term goals are to understand the abnormalities seen in acute myelogenous leukemia (AML), in which differentiation of myeloid blasts is blocked, and to use these myeloid promoters as tools to drive lineage and stage specific expression of heterologous genes in recipient ES cells and transgenic mice, as a step toward gene therapy applications. A related project in the lab is studying the role of transcription factors, including C/EBP alpha and FoxA2, in normal lung differentiation, as well as in lung cancer. Other basic studies are investigating the role of noncoding antisense RNAs in gene regulation. Techniques in the laboratory include analysis of regulation, function, and signaling of transcription factors, transgenic and knockout studies, and gene therapy applications.