Abstract
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-TCL1Tg 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-TCL1Tg;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.
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Acknowledgements
This work was supported by grants from the National Institutes of Health (Grant CA113969 to DAW), the Deutsche Forschungsgemeinschaft (RA 1705/1-1 to IR), the St Baldrick's Foundation (LUWM) and the Leukemia and Lymphoma Society (JCB). Patient samples and IGHV sequence data were obtained through the CLL Research Consortium (CRC).
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YG, JAC, TM and DAW designed research and provided scientific advice; IR, AS-A, DZD, LUWM and VS performed research; IR, AS-A, DZD, LUWM and PJ analyzed data; CMC, DML and JCB contributed vital new reagents; IR, AS-A and DAW wrote the paper.
Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
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Sanchez-Aguilera, A., Rattmann, I., Drew, D. et al. Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia. Leukemia 24, 97–104 (2010). https://doi.org/10.1038/leu.2009.217
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DOI: https://doi.org/10.1038/leu.2009.217
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