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SOFT file
| Title / Description |
Braf inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia, and exert anti-leukemic activity |
| Accession |
GSE63790
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| Summary |
Hairy cell leukemia (HCL) shows unique clinico-pathological and biological features. HCL responds well to purine analogues but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-MEK-ERK pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (Vemurafenib; Dabrafenib) or MEK (Trametinib) inhibitors. Results were validated in vivo in samples from Vemurafenib-treated HCL patients within a phase-2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, TRAP and cyclin-D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by co-culture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL. |
| Organism |
Homo sapiens |
| Platform |
GPL570 |
| Normalized |
False |
| Parsed SOFT file |
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Metadata
| Differential expression method |
Characteristic Direction
|
| Cutoff |
500 |
| Drug_name |
Vemurafenib |
| Smiles |
CCCS(=O)(=O)Nc1ccc(c(c1F)C(=O)c1c[nH]c2c1cc(cn2)c1ccc(cc1)Cl)F |
| Drugbank_id |
DB08881 |
| Cell_type |
Primary leukemic cells (purified from peripheral blood) - 48 Hours |
| Organism |
human |
Visualizations
| Principal Component Analysis |
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| Hierarchical clustering |
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External Links and Downloads
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Gene lists
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Enrichr
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L1000CDS2
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PAEA
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Crowdsourcing |
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