Involvement of RhoH GTPase in the Development of B-Cell Chronic Lymphocytic Leukemia

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 ZAP70 to the immunological synapse. Here we investigated the role of RhoH in the B-cell lineage. B-cell receptor (BCR) signaling was intact in Rhoh(−/−) mice. Since 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 demonstrated a 2.3-fold higher RhoH expression compared to 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 plays a role in the progression of CLL in a murine model and shows RhoH expression is altered in human primary CLL samples.