This is a proposal to continue the investigation of the role of RhoGTPases and their regulatory proteins in hematopoiesis, hematopoietic cell function and hematopoietic malignancies. The RhoGTPases form a large family of proteins that mediate an extensive array of fundamental cellular function including cell division, cell shape, intra-cellular trafficking, cytoskeletal organization, gene transcription, apoptosis, cellular transformation and metastasis. Recently a new member of the RhoGTPase family have been discovered named RhoH, that is expressed specifically only in hematopoietic cells. RhoH was first identified as a fusion protein with bcl6 in non-random translocations involving the RhoH gene at chromosome 4p13 in some cases of lyrnphoma and myeloma. Even more significant is the recent finding that a high frequency of RhoH mutations exist in the Diffuse Large B-Cell Lymphomas (DLCL). This is the first example of the involvement of a RhoGTPase in hematological malignancies, and the clinical importance of the Rho family of proteins. The pathological role of these mutations remain to be clarified. Important clues derived from recent surprising finding showed that RhoH functions as a potent inhibitor of other RhoGTPases. Consistent with RhoH being an """"""""inhibitory"""""""" protein is the recent discovery that a cellular basal level of RhoH is crucial for maintaining T cells in the non-adherant inactive state. RhoH represents a new paradigm for the functional modulation of the RhoGTPases and other related small G-proteins. An important question is what does RhoH do, why does it function differently compared to other RhoGTPases and what is RhoH role in lymphomagenesis? We shall focus our effort to answer the following questions:
Aim1) What is the cellular function of RhoH? ;
Aim2) What is the mechanism of RhoH inhibitory function?;
Aim3) What are the consequences of RhoH mutations in lymphoma? Knowledge from this project will bring new insigths about an important class of proteins that are increasingly implicated in carcinogenesis and cancer progression. The study will also allow us to determine if RhoH is a meaningful variable for prognostication in sub-groups of DLCL and if it can be a useful target for anti-cancer drug development.
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