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Vemurafenib can induce senescence via HIPPO signaling pathway: An alternative targeted therapy against AML and MDS

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231644 | GEO | 2023/05/11

REPOSITORIES: GEO

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Project description:Full Title: Multilineage Dysplasia (MLD) in AML correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: A comparison of 408 cases classified as “AML not otherwise specified” or “AML with myelodysplasia-related changes” The WHO classification of acute myeloid leukemia (AML) is hierarchically structured and integrates genetic information, data on patients’ history, and multilineage dysplasia (MLD). The category “AML with MDS-related changes” (AML-MRC) is separated from AML not otherwise specified (AML-NOS) by the presence of either MLD, MDS-related cytogenetics or MDS history. To clarify whether MLD alone is clinically relevant, we analyzed 408 adult patients categorized as AML-MRC or AML-NOS. EFS (Median 13.8 months vs. 16.0 months) and 3-year-OS (45.8% vs. 53.9%) did not differ significantly between patients with MLD and without. However, MLD correlated with pre-existing MDS (p<0.001) and MDS-related cytogenetics (p=0.035). Patients with MLD as sole AML-MRC criterion (AML-MLD-sole; n=90) had less frequently FLT3-ITD (p=0.032), and a lower median age than AML-NOS (n=232), but EFS, OS, and WBC did not differ significantly. Contrarily, patients with AML-NOS plus AML-MLD-sole (n=323) versus patients with MDS history or MDS-related cytogenetics (n=85) had better EFS (16.9 vs. 10.7 months; p=0.005) and 3-year-OS (55.8% vs. 32.5%; p=0.001). Gene expression profiles were measured for a subset of 96 patients. Analysis of the expression data showed distinct clusters for AML-MLD-sole and AML-NOS versus AML with MDS-related cytogenetics or MDS history. Thus, MLD demonstrated no independent clinical impact, while cytogenetics and MDS history were of prognostic relevance. This data suggest modifications in a revised WHO proposal. All 96 bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation.

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Vemurafenib can induce senescence via HIPPO signaling pathway: An alternative targeted therapy against AML and MDS

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