Prognostic Implications and Biological Roles of RhoH in Acute Myeloid Leukemia.

The Rho family of small GTPases including Rho, Rac, and Cdc42 has been well characterized as molecular switches to transduce signals from plasma membrane to the downstream effectors. Rac1 and Rac2 are known to regulate engraftment and mobilization of hematopoietic stem cells. RhoH, a member of the Rho family, is specifically expressed in hematopoietic cells, and has been reported to inhibit the cell adhesion through regulating Rac and αLβ2 integrin. As RhoH is GTPase deficient and constitutively active, GTP-bound form, the activity of RhoH is directly related to the level of expression. Previous reports demonstrated the aberrant somatic hypermutation of RhoH gene as a novel mechanism of genetic lesion in diffuse large B-cell lymphoma, possibly through the deregulated expression although the role of the RhoH on leukemia is largely unknown. Here we have screened for the expression level of RhoH gene in the bone marrow samples from 90 previously untreated acute myeloid leukemia cases by using a real-time fluorescence detection method. The expression level of RhoH was neither related to the FAB classification, CR rate, nor WBC counts. In addition, the RhoH expression was not associated with the known gene mutations such as N-Ras, FLT3, and p53. However, the multivariate analysis demonstrated that low expression of RhoH was the independent unfavorable prognostic factor for overall and disease free survival (p=0.0028 and 0.003, respectively). RhoH did not affect the affinity modulation of α4β1 integrin, however, RhoH negatively regulate Rac activation in our system, suggesting that RhoH might work as a proapoptic molecule through Rac deactivation. Further investigations would be required to clarify the biological roles of RhoH on leukemic cells.