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