Vemurafenib can induce senescence via HIPPO signaling pathway: An alternative targeted therapy against AML and MDS
The outcome of Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remain dismal despite the development of treatment. Exploration of alternative targeted gene therapy gradually become a new hot field in improving prognosis. We found BRAF was overexpressed in AML and MDS, which is correlated with poor prognosis. The BRAF inhibitor-Vemurafenib (VEM) could significantly induce senescence and therefore resulted in proliferation inhibition and apoptosis of AML cells. Moreover, this inhibitory effect was verified in CD34+ cells derived from AML patients, and enhanced by Bortezomib (BOR). Mechanistically, we showed that VEM combined with BOR could upregulate MST2 and turned on HIPPO signaling pathway, thereby inducing cellular senescence in vitro and vivo. Our data implicated BRAF expression in the biology of AML patients. We reported clinical correlates and provide a potential biological basis for these correlations. Analyzing the expression of BRAF may help predict prognosis and provide potential therapeutic target for AML and MDS patients. Overall design: SAMPLE1 and SAMPLE5 was SKM-1 as control; SAMPLE2 and SAMPLE6 was SKM-1 treated with BOR; SAMPLE3 was SKM-1 treated with VEM;SAMPLE 4 was SKM-1 treated with VEM combined BOR.