Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia

• Published in: Leukemia Vol. 24; no. 1; pp. 97 - 104
• Main Authors: Sanchez-Aguilera, A, Rattmann, I, Drew, D Z, Müller, L U W, Summey, V, Lucas, D M, Byrd, J C, Croce, C M, Gu, Y, Cancelas, J A, Johnston, P, Moritz, T, Williams, D A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2010; Nature Publishing Group
• Subjects: Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Bone marrow; Cancer; Cancer Research; Cells; Chronic lymphocytic leukemia; Critical Care Medicine; Development and progression; Disease Models, Animal; Experimental malignant blood diseases; Extracellular Signal-Regulated MAP Kinases - metabolism; Guanosine triphosphatase; Health aspects; Hematology; Hospitals; Humans; Immunology; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - etiology; Lymphoma; Medical research; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Oncology; original-article; Pathogenesis; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Antigen, B-Cell - physiology; rho GTP-Binding Proteins - physiology; Signal transduction; Transcription Factors - physiology; Transgenic animals; Tumors; ZAP-70 Protein-Tyrosine Kinase - physiology; United States; Germany; United States > US; Ohio; lymphopoiesis; chronic lymphocytic leukemia; TCL1; B cells; RhoH GTPase; Cell proliferation; Lymphopoiesis; Esterases; Carcinogenesis; Hematopoiesis; Lymphoproliferative syndrome; Genetics; Protooncogene; Leukopoiesis; Hematology; Enzyme; Triphosphoric monoester hydrolases; Rodentia; dGTPase; B cell neoplasm; Malignant hemopathy; B-Lymphocyte; TCL1 B cells; Vertebrata; Chronic lymphocytic leukemia; Mammalia; Mouse; Animal; C-Onc gene; Hydrolases; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2009.217

RhoH is a hematopoietic-specific, GTPase-deficient member of the Rho GTPase family that functions as a regulator of thymocyte development and T-cell receptor signaling by facilitating localization of zeta-chain-associated protein kinase 70 (ZAP70) to the immunological synapse. Here we investigated the function of RhoH in the B-cell lineage. B-cell receptor (BCR) signaling was intact in Rhoh −/− mice. Because RhoH interacts with ZAP70, which is a prognostic factor in B-cell chronic lymphocytic leukemia (CLL), we analyzed the mRNA levels of RhoH in primary human CLL cells and showed a 2.3-fold higher RhoH expression compared with normal B cells. RhoH expression in CLL positively correlated with the protein levels of ZAP70. Deletion of Rhoh in a murine model of CLL ( Eμ-TCL1 Tg mice) significantly delayed the accumulation of CD5 + IgM + leukemic cells in peripheral blood and the leukemic burden in the peritoneal cavity, bone marrow and spleen of Rhoh −/− mice compared with their Rhoh +/+ counterparts. Phosphorylation of AKT and ERK in response to BCR stimulation was notably decreased in Eμ-TCL1 Tg ; Rhoh −/− splenocytes. These data suggest that RhoH has a function in the progression of CLL in a murine model and show RhoH expression is altered in human primary CLL samples.