Daniel G. Tenen, M.D.

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.

References:
Tenen DG. Disruption of differentiation in human cancer: AML shows the way. Nature Rev. Cancer 3:89-101, 2003.

Rosenbauer F, Wagner K, Kutok JL, Iwasaki H, Le Beau MM, Okuno Y, Akashi K, Fiering S, Tenen DG. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. 2004: Nature Genet. 36:624-630.

Zhang P, Iwasaki-Arai J, Iwasaki H, Fenyus ML, Dayaram T, Owens BM, Shigematsu H, Levantini E, Huettner CS, Lekstrom-Himes JA, Akashi K, Tenen DG. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor CCAAT Enhancer Binding Protein ?. 2004: Immunity 21:853-863.

Iwasaki H, Somoza C, Shigematsu H, Duprez EA, Iwasaki-Arai J, Mizuno SI, Arinobu Y, Geary K, Zhang P, Dayaram T, Fenyus ML, Elf S, Chan S, Kastner P, Huettner CS, Murray R, Tenen DG, Akashi K. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. 2005: Blood 106:1590-1600.

Steidl U, Steidl C, Ebralidze A, Chapuy B, Han HJ, Will B, Rosenbauer F, Becker A, Wagner K, Koschmieder S, Kobayashi S, Costa DB, Schulz T, O'Brien KB, Verhaak RGW, Delwel R, Haase D, Truemper L, Krauter J, Kohwi-Shigematsu T, Griesinger F, Tenen DG. A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. 2007: J Clin Invest 117:2611-2620.

Huang G, Zhang P, Hirai H, Elf S, Yan X, Chen Z, Koschmieder S, Okuno Y, Dayaram T, Growney JD, Shivdasani RA, Gilliland DG, Speck NA, Nimer SD, Tenen DG. PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. 2008: Nature Genet 40:51-60.

Key aims:
Dr. Tenen's laboratory focuses on gene regulation and its relationship to differentiation. Some key projects include:

1. Identification of key target genes in leukemia and lung cancer. Among these include transcription factors such as PU.1 and C/EBP alpha, genes which themselves are critical for normal blood development, and not infrequently mutated or downregulated in leukemia.
2. Development of novel therapies for leukemia and lung cancer based on these key target genes. These include studies of the effects of all trans retinoic acid (ATRA) on gene regulation and differentiation, various tyrosine kinase inhibitors currently being used in clinical studies, such as inhibitors of the BCR/ABL and FLT3-ITD kinases, as well as developing novel drug screens to identify new compounds capable of inducing leukemic cell differentiation based on altering gene regulation function. Finally, current efforts also include novel studies of manipulation of gene expression using micro RNA and alteration of naturally occurring antisense RNAs.
3. Basic studies understanding gene regulation in hematopoietic cells, including hematopoietic stem cells. These studies are also aimed at developing novel ways of manipulating gene expression in stem cells. Finally, these studies include comparison of mechanisms in both normal and leukemic stem cells, with the ultimate aim of understanding differences between normal and leukemic stem cells as a basis for targeted cancer stem cell therapy.

Biosketch:
Daniel G. Tenen is Professor of Medicine at Harvard Medical School, as well as Director of the Blood Program of the Harvard Stem Cell Institute, Director of the Cancer Biology Program at Beth Israel Deaconess Medical School, co-Director of the Harvard Medical School Hematology Training Grant, and Distinguished Visiting Professor at the National University of Singapore. His research efforts have focused on transcription factors, gene regulation, and their role in normal differentiation and cancer. His research contributions have included establishing the role of transcription factors in differentiation of myeloid cells and the role of disruption of these pathways in leukemia and lung cancer. He was born and raised in Los Angeles and received his B.A. from the University of California at Los Angeles in 1967. He subsequently moved to Boston, received his M.D. degree from Harvard Medical School in 1975. He completed training in Internal Medicine at Brigham & Women's Hospital and Medical Oncology at Dana Farber Cancer Institute, and his research training as a postdoctoral fellow in David Livingston's laboratory at Dana Farber Cancer Institute. He established his own independent laboratory at Beth Israel Deaconess Medical School, Harvard Medical School, in 1984.