The goal of this project is to identify mechanisms mediating effects of endogenous TGF-b1 on the development, function, and malignant transformation of hematopoietic cells, with a primary emphasis on lymphoid lineages. Experimental evidence from in vitro studies of function suggest a critical role for TGF-b1 in regulating myelopoiesis and immune cell function, but such studies are limited by their inability to reproduce the complex in vivo network which ordinarily influences the genesis and function of these cell populations. Our approach to this problem has been to utilize the TGF-b1-null mouse, as well as complimentary vivo model systems characterized by a disruption in genes encoding components of the TGF-b signaling pathway. This approach has enabled us to identify critical links between cell cycle control by TGF-b1, immune cell maturation and function, and hematopoietic cell growth and differentiation, as they occur in vivo. Examples include our demonstration of myeloid hyperplasia as a distinct phenotype in TGF-b1-null mice, and of novel autocrine effects of TGF-b1 in the autoimmune and hematopoietic manifestations of TGF-b1 deficiency. Our collaborative efforts have led to important discoveries regarding the: epidermal dendritic cell (DC) requirement for TGF-b1 (Mark Udey, NCI) and DC antigen trafficking (Shin-Ichi Hayashi, Tottori University); role of the TGF-b1-intermediate Smad3 in mucosal immunity, T cell function, T cell leukemogenesis, chemotaxis, MCH class II and class II transactivator expression, and in suppression of IL-2 expression (Chuxia Deng, NIH; Frank Balis and Peter Aplan, NIH; Tika Benvinista, UAB); role of TGF-b in plasmacytomagenesis (Mike Potter, NCI; John Shaughnessy, Univ.Arkansas); TGF-b-independent effects of CTLA4 (Jim Allison, U.C. Berkeley); haploinsufficient tumor suppressor function of TGF-b1 (Lalage Wakefield, NCI and Andy Koff, Memorial Sloan Kettering); and a role of p21cip1 in activated immune cells and of TGF-b in intestinal tumorigenesis (Chuxia Deng, NIH). To define the molecular events through which TGF-b governs hematopoietic stem cell differentiation and commitment, we are developing new approaches that include conditional and lineage-specific disruption of the TGF-b ligand and signaling intermediates. This includes models in which pathway specific intermediates are conditionally deleted in the T cell lineage. Finally, we maintain an emphasis on translational research, aiming to move our observations toward development of useful clinical tools and potential therapies. As part of this effort, our laboratory is the first to successfully develop functionalized, biologically active epitope-tagged TGF-b proteins and to design diagnostic and potential therapeutic approaches based on the application of such proteins. More importantly, these reagents will prove invaluable in developing new transgenic models in which epitope-tagged TGF-b isoforms can be expressed in a spatially and/or temporally restricted manner. Future studies employing systemic administration of TGF-b either in disease models or in the clinic will benefit from the availability of a readily detectable epitope-tagged-TGF-b. In addition, we are the recipient of a 2003 intramural Research Award which supports currents efforts to develop TGF-b antagonists as agents that can enhance bone marrow recovery following myeloablative chemotherapy. We are a collaborator on an active CRADA with Genzyme Corporation which supports the evaluation of specific and novel TGF-b antagonists for this application.
We aim to test this hypothesis in preclinical models and to focus on translating this effort into clinical trials in the near future.
| Mamura, Mizuko; Lee, WoonKyu; Sullivan, Timothy J et al. (2004) CD28 disruption exacerbates inflammation in Tgf-beta1-/- mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-beta1. Blood 103:4594-601 |
| Wolfraim, Lawrence A; Fernandez, Tania M; Mamura, Mizuko et al. (2004) Loss of Smad3 in acute T-cell lymphoblastic leukemia. N Engl J Med 351:552-9 |
| Kim, S-J; Letterio, J (2003) Transforming growth factor-beta signaling in normal and malignant hematopoiesis. Leukemia 17:1731-7 |
| Cao, Zhouhong; Flanders, Kathleen C; Bertolette, Daniel et al. (2003) Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells. Blood 101:498-507 |
