Prognostic implication and biological roles of RhoH in acute myeloid leukaemia
Prognostic implication and biological roles of RhoH in acute myeloid leukaemia
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DOI：
10.1111/j.1600-0609.2008.01132.x
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发表时间：
2008-12-01
影响因子：
3.1
通讯作者：
Naoe, Tomoki
中科院分区：
文献类型：
--
作者：
Iwasaki, Toshihiro;Katsumi, Akira;Naoe, Tomoki
Rho家族的小GTP酶，包括Rho，Rac和Cdc 42，已被很好地表征为将信号从质膜转导到下游效应物的分子开关。RhoH基因是Rho家族的成员，在造血细胞中特异性表达。RhoH的已知功能是拮抗Rac并介导T淋巴细胞中ZAP-70的活化;然而，RhoH在骨髓细胞中的生物学作用仍然未知。在这里，我们分析了90例新诊断的急性髓系白血病（AML）患者骨髓样本中RhoH基因转录本的表达水平的预后意义，使用实时荧光检测方法。Kaplan-Meier分析表明RhoH转录本的低表达是总体和无病生存期预后不良的预测因子。多因素分析显示RhoH低表达是AML患者总体生存率和无病生存率的独立不利预后因素。RhoH的过表达可能通过Rac的失活导致Bad在丝氨酸75位残基的去磷酸化。RhoH的低表达（即高GTP-Rac）可能有助于白血病细胞中的化疗抗性。我们的研究结果表明，抑制Rac及其信号传导成分可能提供一个有用的抗白血病的策略。
The Rho family of small GTPases, including Rho, Rac and Cdc42, has been well characterised as a molecular switch that transduces signals from plasma membrane to the downstream effectors. RhoH gene, a member of the Rho family, is specifically expressed in haematopoietic cells. The known function of RhoH is antagonising Rac and mediating activation of ZAP-70 in T lymphocytes; however, biological roles of RhoH in myeloid cells remain unknown. Here, we analysed the prognostic implication of the expression level of the RhoH gene transcript in bone marrow samples from 90 newly diagnosed acute myeloid leukaemia (AML) patients using a real-time fluorescence detection method. Kaplan-Meier analysis demonstrated that low expression of the RhoH transcript was a predictor of worse prognosis in both overall and disease-free survival. Multivariate analysis demonstrated that low expression of RhoH was an independent unfavourable prognostic factor for both overall and disease-free survival of AML patients. Overexpression of RhoH leads to dephosphorylation of Bad at Serine 75 residue possibly through deactivation of Rac. It is possible that low expression of RhoH (i.e. high GTP-Rac) contributes to chemotherapy resistance in leukaemia cells. Our result suggests that inhibition of Rac and its signalling components might provide a useful anti-leukaemic strategy.