The Role of RUNX Family Transcription Factors in Immune System Development
All of the cells of the blood descend from the progeny
of hematopoietic stem cells resident in the bone marrow. Hematopoietic
stem cells are very long-lived: they survive and divide for the life
of the organism. Their daughter cells go through a period of development
in which they become more and more specialized, turning on and off the
expression of specific genes, until they are fully differentiated. The
subversion of this process of normal development often results in cancer.
My laboratory is interested in how the regulation of gene expression
by the RUNX family of transcription factors influences the development
and cancerous transformation of cells of the immune system.
RUNX family transcription factors (RUNX1, RUNX2, and RUNX3) bind to
DNA and other proteins to activate or suppress transcription of specific
genes. We have previously found that expression of RUNX1 has profound
effects on the development of T cells and the myeloid cells known as
neutrophils. We use a retroviral expression system that allows us to
express normal and mutated RUNX proteins in both primary cells and cell
lines, which can then be cultured. The projects currently pursued by
my laboratory include:
- We have found that the expression of RUNX1 in the myeloid cell line
32Dcl3 promotes the cells’ continued proliferation, which is
reminiscent of the high proportion of immature proliferating myeloid
cells seen in patients with the cancer acute myelogenous leukemia.
The fact that increased expression of RUNX1 in humans is associated
with a predisposition to develop acute myelogenous leukemia supports
our hypothesis that an increase of RUNX1 expression in immature myeloid
cells leads to a pre-cancerous state of extended proliferative capacity.
We will express mutated forms of RUNX1 in 32Dcl3 cells and primary
myeloid cells to discover the mechanism by which RUNX1 works.
- We have found that expression of the transcription factor RUNX1
suppresses the development of gamma delta T cells (Fig. 1 gd
TCR) and silences the expression of CD4 specifically at the immature
alpha beta TCR double-positive thymocyte stage (Fig. 2 ab
TCR DP). This leads to a bias first towards the production of ab
T cells and later, to a bias towards the production of CD8 cytotoxic
T cells (Fig. 1 CD8+ TCRbhi). RUNX1 is the first transcription factor
known to influence production of either of these types of T cells.
It is important to understand how production of different kinds of
T cells is regulated: for instance, one can see from AIDS that neither
gd T cells nor CD8+ ab
T cells can make up for the lack of CD4+ ab
T cells. We are characterizing the nature of RUNX family member regulation
of CD4 expression, seeking to identify RUNX gene targets in early
thymocytes, and investigating what signals normally control the level
of RUNX family members in thymocytes.
- RUNX1 is associated with the development of pediatric acute lymphoblastic
leukemia (ALL). We have discovered truncated splice isoforms of RUNX1
that, when expressed via retroviral transduction in immature thymocytes,
cause a proliferative expansion or give a survival advantage to these
cells. We have localized this effect to a short domain in the N-terminus
of RUNX1 and are working on identifying specific amino acids and potential
interacting proteins responsible for this effect.
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Thymocyte Development
Arrows indicate the direction and timing of branches in the thymocyte
maturation pathway, which involves natural killer cells (NK, orange),
gamma delta T cells (gd TCR, green), alpha
beta T cells (ab TCR, blue and purple), immature
"double-negative" thymocytes (DN1-DN4), "double-positive"
thymocytes expressing both the CD4 and CD8 proteins (DP, light blue),
and "single-positive" thymocytes expressing either CD4 or
CD8 proteins (SP, blue or purple).
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Publications
Telfer J. C. and C. E. Rudd (1991) A 32-kD GTP-binding protein associated
with the CD4-p56lck and CD8-p56lck T-cell receptor complexes. Science
254, 439-441.
Rudd C.E., Janssen O., Prasad K.V.S., Raab M., Dasilva A., Telfer
J.C., and H. Yamamoto (1993) Src-related protein-tyrosine kinases and
their surface receptors. Biochimica et Biophysica Acta 1155,
239-266.
Telfer J.C., Janssen O., Prasad K. V. S., Raab M., DaSilva A.,
and C. E. Rudd (1995) Src-related kinases and their receptors in T cell
activation. T-cell Receptors, J. Bell, M. Owen and E. Simpson (Ed.),
Oxford University Press, pp. 164-193.
Rothenberg E.V., Telfer J.C., and M.K. (Anderson 1999) Transcriptional
regulation of lymphocyte lineage commitment. BioEssays 21, 726-742.
Telfer J.C. and Rothenberg, E.V. (2001) Expression and function of a
stem cell promoter for the murine CBFa2 (runx1) gene: distinct roles
and regulation in natural killer and T cell development. Dev. Biol.
229, 363-382 (available online at www.idealibrary.com
doi:10.1006/dbio.2000.9991).
Telfer J.C., Laurent M.N., and E.V. Rothenberg (2002) Runx1 expression
suppresses the expression of CD4 in immature double-positive CD4+CD8+
thymocytes. (manuscript submitted)
Rothenberg E.V., Yui M.A., and J.C. Telfer (2002) T cell Developmental
Biology. Fundamental Immunology, 5th edition, edited by W. Paul.
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