{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRhoH is an atypical member of the Rho GTPase family whose expression is strictly confined to hematopoietic cells. Its unique regulation—marked by heterogeneous 5′ transcripts and alternative splicing events—may underlie its deregulation in certain hematological malignancies and account for its atypical behavior as it lacks intrinsic GTPase activity, remaining constitutively active. These features position RhoH as a potential antagonist of Rac signaling and a key modulator within hematopoietic lineages."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn T lymphocytes, RhoH plays an essential adaptor role in T-cell receptor (TCR) signaling by facilitating the localization of kinases such as ZAP70 to the immunological synapse. This function is critical for both positive and negative thymic selection and for proper downstream signaling upon antigen encounter. Notably, engagement of the TCR triggers rapid lysosomal degradation of RhoH, suggesting that tight post-activation regulation of RhoH levels is required to prevent excessive signaling. Consistent with these observations, patients with RHOH mutations exhibit T-cell deficiencies and associated immunodeficiencies, demonstrating its central role in adaptive immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its fundamental roles in T-cell biology, aberrant RhoH expression has been implicated in malignant processes and in the regulation of cell migration and differentiation within the hematopoietic compartment. In hairy cell leukemia, for instance, underexpression of RhoH is linked to pathogenic cell adhesion and transendothelial migration, and restoration of RHOH expression can inhibit these aberrant behaviors. Similarly, loss of RhoH in chronic lymphocytic leukemia disrupts integrin-mediated signaling, leading to impaired homing and migration of leukemic cells. RhoH also modulates cytokine responses, as demonstrated by its involvement in IL-3–dependent STAT activation, and interacts with transcriptional regulators like Kaiso to coordinate actin cytoskeletal dynamics necessary for chemokine-driven migration. Finally, RhoH serves as a negative regulator of eosinophil differentiation by modulating GATA-2 expression, thereby influencing hematopoietic lineage specification."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sébastien Lahousse, Anne-Lise Smorowski, Claude Denis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural features of hematopoiesis-specific RhoH/ARHH gene: high diversity of 5'-UTR in different hematopoietic lineages suggests a complex post-transcriptional regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2004.08.022"}], "href": "https://doi.org/10.1016/j.gene.2004.08.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15563831"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15563831"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Toshihiro Iwasaki, Akira Katsumi, Hitoshi Kiyoi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prognostic implication and biological roles of RhoH in acute myeloid leukaemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Haematol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1600-0609.2008.01132.x"}], "href": "https://doi.org/10.1111/j.1600-0609.2008.01132.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18691253"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18691253"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Anja Troeger, David A Williams "}, {"type": "b", "children": [{"type": "t", "text": "Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2013.07.002"}], "href": "https://doi.org/10.1016/j.yexcr.2013.07.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23850828"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23850828"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "A Sanchez-Aguilera, I Rattmann, D Z Drew, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/leu.2009.217"}], "href": "https://doi.org/10.1038/leu.2009.217"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19847197"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19847197"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jan Schmidt-Mende, Barbara Geering, Shida Yousefi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lysosomal degradation of RhoH protein upon antigen receptor activation in T but not B cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Immunol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/eji.200939556"}], "href": "https://doi.org/10.1002/eji.200939556"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19950172"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19950172"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Amandine Crequer, Anja Troeger, Etienne Patin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI62949"}], "href": "https://doi.org/10.1172/JCI62949"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22850876"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22850876"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sylvie Galiègue-Zouitina, Laure Delestré, Caroline Dupont, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Underexpression of RhoH in Hairy Cell Leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-07-5661"}], "href": "https://doi.org/10.1158/0008-5472.CAN-07-5661"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18559497"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18559497"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Mehtap S Gündogdu, He Liu, Daniela Metzdorf, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The haematopoietic GTPase RhoH modulates IL3 signalling through regulation of STAT activity and IL3 receptor expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1476-4598-9-225"}], "href": "https://doi.org/10.1186/1476-4598-9-225"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20738848"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20738848"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Anja Troeger, Amy J Johnson, Jenna Wood, et al. 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