Recurrent chromosomal rearrangements in the human RhoH gene locus have been identified in non-Hodgkin's lymphomas and multiple myeloma, and somatic hypermutation in the gene has also been found in 45% of the diffuse large B-cell lymphomas. The cytogenetic and mutational mapping analyses of these patient samples suggest the intriguing possibility that dysregulated expression of RhoH may contribute to abnormal cell proliferation and survival in lymphomas. The RhoH gene encodes a novel hematopoietic specific member of the Rho GTPase family. This is the first report of mutations of a Rho GTPase, at such a high frequency, in human cancer. Rho GTPases are well characterized as critical regulators of growth control and actin cytoskeleton reorganization in many cells including blood cells. RhoH is GTPase-deficient and therefore remains in an active, GTP-bound state. Thus, the activity of RhoH is likely dependent on expression levels of the protein. In this grant, we propose to study the mechanism of regulation of the RhoH expression/activity during hematopoiesis and elucidate the role(s) and mechanism of RhoH in controlling growth, differentiation, transformation and related intracellular signaling pathways in hematopoietic cells.
Specific aim 1 will determine the expression of RhoH in B lymphoid lineage, and identify the critical regulatory elements controlling its lineage-specific expression.
In specific aim 2, we will study the role of RhoH in hematopoietic and immune cell proliferation and function using retrovirus-mediated gene transfer. Bone marrow transplantation assays will further provide us valuable in vivo information and may potentially lead to the development of a mouse model of RhoH-related hematologic disease.
In specific aim 3, we will investigate RhoH-mediated signaling pathways that are critical in regulation of hematopoietic cell proliferation and function and determine the functional crosstalk between RhoH and Rac GTPases in hematopoietic cells. These biological experiments may provide detailed information critical to complement, further interpret and provide mechanistic insights into previously findings of RhoH as a hypermutable gene in human lymphomas. Given the lineage-restricted expression of RhoH such an observation could have important therapeutic implication.
| Gu, Yi; Chae, Hee-Don; Siefring, Jamie E et al. (2006) RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol 7:1182-90 |
| Gu, Y; Siefring, J E; Wang, L et al. (2006) Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation. Oncogene 25:3963-72 |
