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Fotini Gounari, Ph.D.
Thymocyte Development and Transformation
Research Summary
Unlike other hematopoietic lineages that complete their developmental
process in the bone marrow, T-cell development requires an obligatory
travel of progenitors to the thymus where commitment and maturation to
the T-cell lineage takes place. Our lab focuses on signaling
pathways whose function and disfunction can explain the physiology and
pathology of T cell development. The assembly and function of the
pre-T cell receptor (pre-TCR), marks commitment to the alphabeta-T cell
lineage, through molecular events that are poorly understood. We
have shown that activation of the wnt/beta-catenin pathway promotes T
cell maturation in the absence of the pre-TCR, and therefore may act
downstream the pre-TCR signaling, it also stalls thymocyte development
at the DP stage acting downstream alphabeta-TCR signaling.
Uncontrolled beta-catenin activity predisposes thymocytes to
transformation leading to thymic Lymphomas. Activation of
wnt/beta-catenin signaling has been proposed to drive self-renewal of
hematopoietic stem cells, the source of all cell lineages in the blood,
and is known to be the initiating event in colon cancer, promoting
expansion of aberrant stem cells. T cell development is also
critically dependent on Notch signaling, while its deregulated
activation has been associated with human T-cell leukemias, and with
acute leukemia in mice. These leukemias require preTCR
signaling. All together, these observations suggest that the
pre-TCR lies at the crossroad to at least two major signaling pathways,
whose cross talk is central both for development and malignant
transformation of T cells: wnt/beta-catenin and Notch.
Research in my lab aims at clarifying the cross talk between the
signals emanating from the pre-TCR, wnt/beta-catenin, and Notch
pathways, using transgenic animals as well as in vitro
techniques. Animal models engineered to express the pre-TCR in an
inducible manner are used to examine whether the pre-TCR directly
modulates the other two pathways, or is acting in parallel. We
examine whether leukemias caused by wnt/beta-catenin like those induced
by Notch, require or benefit from the action of pre-TCR or the
alphabeta TCR. Finally, we are examining the interdependence of
these three pathways in promoting T cell development and inducing
leukemia. Defining the precise role of wnt/beta-catenin and Notch and
their interconnection with pre-TCR signaling in T cell development will
open new horizons in our understanding of the controlled transition of
hematopoietic stem cells into the mature alphabeta T cell lineage.
Defining the role of pre-TCR signaling and its cross talk with other
two pathways in leukemia, will highlight potential targets for
therapeutic intervention in the cascade of events that promote and
maintain T cell leukemias.
Selected Papers
Martin C.H., Aifantis I., Scimone
M.L., von Andrian U.H.,
Reizis B., von Boehmer H., and Gounari F. Efficient thymic immigration
of B220+
lymphoid-restricted bone marrow cells with T precursor potential. Nat
Immunol.
4: 866-873, (2003).
Borowski
C., Li X., Aifantis I., Gounari F., and von
Boehmer H. PreTCR a and TCR a are not interchangeable partners of TCRb
during T
lymphocyte development. Journal of Experimental Medicine 199: 607-15.
(2004).
Karagianni N, Ly MC, Psarras S, Chlichlia K, Schirrmacher V, Gounari F,
Khazaie K. Novel adenomatous polyposis coli gene promoter is located 40
kb upstream of the initiating methionine. Genomics. 85: 231-237 (2005).
Gounari F.*, Chang R., Cowan J., Guo Z., Dose M., Gounaris E. &
Khazaie K. Loss of the Adenomatous-Polyposis-Coli gene function
disrupts thymic development. Nat. Immunol. 6: 800-809. (2005).
Garbe A. I., Krueger A., Gounari F., Zuniga-Pflucker J-C. and von
Boehmer H. Differential synergy of Notch and T cell receptor signaling
determines versus lineage fate. Journal of Experimental Medicine
203: 1579-90. (2006).
Dose M., Khan I., Guo Z., Kovalovsky D., Krueger A., von Boehmer H.,
Khazaie K., and Gounari F.* c-Myc mediates preTCR induced proliferation
but not developmental progression. Blood 108: 2669- 2677. (2006).
Guo Z, Dose M, Kovalovsky D, Chang R, O'Neil J, Look AT, von Boehmer H,
Khazaie K, Gounari F. * Beta-catenin stabilization
stalls the transition from double-positive to single-positive stage and
predisposes thymocytes to malignant transformation. Blood. 109:
5463-72. (2007).
Mao C, Tili EG, Dose M, Haks MC, Bear SE, Maroulakou I, Horie K,
Gaitanaris GA, Fidanza V, Ludwig T, Wiest DL, Gounari F, Tsichlis PN.
Unequal contribution of Akt isoforms in the double-negative to
double-positive thymocyte transition. J Immunol. 178: 5443-53. (2007).
Gounaris E, Erdman SE, Restaino C,
Gurish MF, Friend DS,
Gounari F, Lee DM, Zhang G, Glickman JN, Shin K, Rao VP, Poutahidis T,
Weissleder R, McNagny KM, Khazaie K. Mast cells are an essential
hematopoietic
component for polyp development. Proc Natl Acad Sci Usa 104: 19977-82.
(2007).
Gounari, F. and Dose, M. Lef-1:
NOTCHed up in T-cell
lymphomas Blood 110:2227. (2007).
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