The newly defined RhoH gene has been demonstrated to be mutated in lymphoma samples. These alterations include chromosomal rearrangements and a high frequency of somatic mutations (up to 46 percent) in non-Hodgkin's lymphomas and diffuse large B-cell lymphoma. The RhoH gene encodes a novel hematopoietic-specific member of the RhoE subfamily, which is GTPase-deficient. Therefore RhoH does not cycle between GDP-bound and GTP-bound states and remains permanently in the active state. Thus the activity of RhoH is likely directly related to the level of the protein expressed in the cell. Previous studies have not directly measured RhoH expression in hematopoietic tumors. The biological role of RhoH in normal and malignant hematopoietic cell development and function have also not been studied. We hypothesize that expression level of RhoH is critical for its biological function in normal hematopoiesis and dysregulated expression may contribute to the transformed phenotypes in human lymphomas. Preliminary data support this hypothesis, since overexpression of RhoH results in abnormal proliferation and actin-based function of primary hematopoietic cells. In this grant, we propose to use a mouse model to elucidate the role and mechanism of RhoH in controlling growth, differentiation, transformation and related signaling pathways in hematopoietic cells, and examine functional interactions between RhoH, Rac and downstream effectors, group A Paks. In addition to this genetic approach, we will assess RhoH expression levels and their correlation with somatic mutations in the human RhoH gene and clinical phenotypes in diffuse large-B cell lymphomas.
Specific Aim 1 will determine the role of RhoH in normal and malignant hematopoietic cells.
In Specific Aim 2, we will determine RhoH-mediated signaling pathways that are critical in regulation of hematopoietic cell proliferation and function.
In Specific Aim 3, we will examine the essential function of RhoH and its interaction with Rac using RhoH-deficient and Rac-deficient compound mice. These biological experiments may provide mechanistic insights and biological context to the previous findings of RhoH as a hypermutable gene in human cancer and possibly establish an animal model for Rho GTPases in tumorigenesis. Given the lineage-restricted expression of RhoH such an observation could also have important therapeutic implication.
|Gordon, P M; Dias, Stuart; Williams, D A (2014) Cytokines secreted by bone marrow stromal cells protect c-KIT mutant AML cells from c-KIT inhibitor-induced apoptosis. Leukemia 28:2257-60|
|Ciuculescu, Marioara F; Brendel, Christian; Harris, Chad E et al. (2014) Retroviral transduction of murine and human hematopoietic progenitors and stem cells. Methods Mol Biol 1185:287-309|
|Troeger, Anja; Chae, Hee-Don; Senturk, Mumine et al. (2013) A unique carboxyl-terminal insert domain in the hematopoietic-specific, GTPase-deficient Rho GTPase RhoH regulates post-translational processing. J Biol Chem 288:36451-62|
|Troeger, Anja; Williams, David A (2013) Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders. Exp Cell Res 319:2375-83|
|Troeger, Anja; Johnson, Amy J; Wood, Jenna et al. (2012) RhoH is critical for cell-microenvironment interactions in chronic lymphocytic leukemia in mice and humans. Blood 119:4708-18|
|Crequer, Amandine; Troeger, Anja; Patin, Etienne et al. (2012) Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections. J Clin Invest 122:3239-47|
|Chang, Kyung Hee; Sanchez-Aguilera, Abel; Shen, Shuhong et al. (2012) Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival. Blood 120:800-11|
|Sanchez-Aguilera, A; Rattmann, I; Drew, D Z et al. (2010) Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia. Leukemia 24:97-104|
|Chae, Hee-Don; Siefring, Jamie E; Hildeman, David A et al. (2010) RhoH regulates subcellular localization of ZAP-70 and Lck in T cell receptor signaling. PLoS One 5:e13970|
|Pai, Sung-Yun; Kim, Chaekyun; Williams, David A (2010) Rac GTPases in human diseases. Dis Markers 29:177-87|
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