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Acute Leukemias

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

Leukemia volume 24, pages 97–104 (2010)Cite this article

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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Author notes

  1. A Sanchez-Aguilera and I Rattmann: These two authors contributed equally to this work.

Authors and Affiliations

  1. Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    A Sanchez-Aguilera, I Rattmann, D Z Drew, L U W Müller, V Summey, Y Gu, J A Cancelas, T Moritz & D A Williams

  2. Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA, USA

    A Sanchez-Aguilera, L U W Müller & D A Williams

  3. Division of Hematology & Oncology, Ohio State University, Columbus, OH, USA

    D M Lucas & J C Byrd

  4. Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH, USA

    C M Croce

  5. Clinical Research Program, Children's Hospital Boston, Boston, MA, USA

    P Johnston

  6. Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Duisburg-Essen Medical School, Essen, Germany

    T Moritz

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  1. A Sanchez-Aguilera
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Corresponding author

Correspondence to D A Williams.

Additional information

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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