Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by increased susceptibility to specific human papillomaviruses, the betapapillomaviruses. These EV-HPVs cause warts and increase the risk of skin carcinomas in otherwise healthy individuals. Inactivating mutations in epidermodysplasia verruciformis 1 (EVER1) or EVER2 have been identified in most, but not all, patients with autosomal recessive EV. We found that 2 young adult siblings presenting with T cell deficiency and various infectious diseases, including persistent EV-HPV infections, were homozygous for a mutation creating a stop codon in the ras homolog gene family member H (RHOH) gene. RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells. Patients' circulating T cells contained predominantly effector memory T cells, which displayed impaired TCR signaling. Additionally, very few circulating T cells expressed the β 7 integrin subunit, which homes T cells to specific tissues. Similarly, Rhoh-null mice exhibited a severe overall T cell defect and abnormally small numbers of circulating β 7 -positive cells. Expression of the WT, but not of the mutated RHOH, allele in Rhoh -/-hematopoietic stem cells corrected the T cell lymphopenia in mice after bone marrow transplantation. We conclude that RHOH deficiency leads to T cell defects and persistent EV-HPV infections, suggesting that T cells play a role in the pathogenesis of chronic EV-HPV infections.

Overexpression of survivin in BCP-ALL identifies patients with a high risk of early relapse. Upon confirmation in a prospective analysis, survivin expression may, in the future, serve to further refine treatment stratification with intensification of therapy in those patients prone to relapse.

The small guanosine triphosphotases (GTPases) Rho proteins are members of the Ras-like superfamily. Similar to Ras, most Rho GTPases cycle between active GTP-bound, and inactive GDP-bound conformations and act as molecular switches that control multiple cellular functions. While most Rho GTPases are expressed widely, the expression of Rac2 and RhoH are restricted to hematopoietic cells. RhoH is an atypical GTPase that lacks GTPase activity and remains in the active conformation. The generation of mouse knock-out lines has led to new understanding of the functions of both of these proteins in blood cells. The phenotype of these mice also led to the identification of mutations in human RAC2 and RHOH genes and the role of these proteins in immunodeficiency diseases. This review outlines the basic biology of Rho GTPases, focusing on Rac and RhoH and summarizes human diseases associated with mutations of these genes.

IntroductionIn patients with chronic lymphocytic leukemia (CLL) the characteristic accumulation of monoclonal mature B lymphocytes in the peripheral blood (PB), bone marrow (BM), and secondary lymphoid tissues (SLTs) is mostly attributed to defective in vivo apoptosis, whereas these cells undergo rapid cell death in vitro. 1,2 It has been demonstrated that ex vivo coculture of CLL cells with stromal cells enhances their survival, and a fraction of CLL cells proliferate in close contact with T lymphocytes and stromal cells within pseudofollicles. 3 Therefore, close contact to accessory cells in the BM and SLTs may contribute to their sustained in vivo survival. 2 This is further supported by the observation that CD38 expression associated with adverse outcome in CLL is up-regulated in response to activated T cells, and thus increased in tissues containing pseudofollicles. 4 In long-term in vitro cultures of PB mononuclear cells (PBMNCs) from CLL patients, an adherent cell population, called "nurse-like" cells (NLCs) can be obtained. 5 These NLCs express and produce chemokines, such as CXCL12 and CXCL13, which regulate trafficking of human CLL cells between PB, lymphoid organs, and BM, and thus promote interaction with the microenvironment necessary for their survival and proliferation. 6,7 Furthermore, matrix metalloproteinase-9 is upregulated in response to integrin, CXCL12, and CCR7 signaling via Erk activation in CLL cells and regulates migration and lymph node infiltration thereby contributing to disease progression. 8 Trafficking, directed migration and homing are complex processes that involve the coordinate activation of Rho GTPases, such as Rac and RhoA downstream of integrins, and chemokine receptors in lymphocytes. 9 Their activity varies in a cell and agonist-specific fashion and is dependent in part on their intracellular localization. 10 In this regard, the Src nonreceptor tyrosine kinase and its target focal adhesion kinase (FAK) are critical regulators of both RhoA and Rac. 11 RhoH, a hematopoietic-specific member of the RhoE/Rnd3 subfamily of GTPases was initially identified as hypermutable gene and translocation partner in human B-cell lymphomas suggesting its involvement in the pathogenesis of B-cell malignancies. [12][13][14][15] Rhoh Ϫ/Ϫ mice exhibit a profound T-cell defect because of impaired T-cell receptor (TCR)-mediated selection and maturation of thymocytes as RhoH is required for CD3 phosphorylation and recruitment of the protein tyrosine kinases Zap70 and Lck to the cellular membrane and immunologic synapse. [16][17][18][19] Although the functional importance of RhoH has been well defined in T cells, its role in B-cell development appears less clear. However, in human CLL samples RhoH expression correlates with expression of the unfavorable prognostic marker Zap70. We previously reported an attenuated disease onset in the absence of RhoH in an E-TCL1 Tg mouse model of CLL, 20 which seemed paradoxical given the lack of RhoH involvement in normal B-cell development and the severe T-cel...