BRAF MUTATIONS IN HAIRY CELL LEUKEMIA
By E. Tiacci, V. Trifonov, G. Schiavoni, A. Holmes, W. Kern, M. Martelli, A. Pucciarini, B. Bigerna, R. Pacini, Victoria A. Wells and 26 more. New England Journal of Medicine, 2011
1,059 citations recorded by the source corpus.
Background Hairy cell leukemia (HCL) is a well defined clinico-pathological entity whose underlying genetic lesion is still obscure. Methods We searched for HCL-associated mutations by massively parallel sequencing of the whole exome of leukemic and matched normal mononuclear cells purified from the peripheral blood of one patient with HCL. Results Whole exome sequencing identified 5 missense somatic clonal mutations that were confirmed at Sanger sequencing, including a heterozygous V600E mutation involving the BRAF gene. Since the BRAF V600E mutation is oncogenic in other tumors, further analyses were focused on this genetic lesion. Sanger sequencing detected mutated BRAF in 46/46 additional HCL patients (47/47 including the index case; 100%). None of the 193 peripheral B-cell lymphomas/leukemias other than HCL that were investigated carried the BRAF V600E mutation, including 36 cases of splenic marginal zone lymphomas and unclassifiable splenic lymphomas/leukemias. Immunohistological and Western blot studies showed that HCL cells express phospho-MEK and phospho-ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic cells from 5 HCL patients with PLX-4720, a specific inhibitor of active BRAF, led to marked decrease of phosphorylated ERK and MEK. Conclusions The BRAF V600E mutation was present in all HCL patients investigated. This finding may have relevant implications for the pathogenesis, diagnosis and targeted therapy of HCL (Funded by the Associazione Italiana Ricerca Cancro and others).
Subfields: Genetics, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/60b39d3e05dfeb023a190168eb15c39df4cbb9f1
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Citations in the corpus
- Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations (2015, neutral): “(%) 2 (11) 5 (50) 7 (27) 3 (38) 0 4 (57)”
- The 2016 revision of the World Health Organization classification of lymphoid neoplasms. (2016, background): “Whereas the2008monograph reported that “No cytogenetic abnormality is specific for [hairy cell leukemia]”, we now know that BRAFV600Emutations are found in almost all cases of hairy cell leukemia (HCL) but not in HCL-variant (HCL-v) or other small B-cell lymphoid neoplasms.(33) More recently, mutati”
- Mutations driving CLL and their evolution in progression and relapse (2015, neutral): “This finding suggests further therapeutic exploration of MAPK-ERK pathway inhibitors in CLL. Intriguingly, BRAF mutations in CLL did not involve the canonical hotspot (V600E) seen in other malignancies 5,13,14 , but rather clustered heavily around the activation segment of the kinase domain ( Fig.”
- Cytokines in Cancer Immunotherapy (2011, background): “The particular importance of this action is suggested by an intriguing parallel recently discovered between HCL and melanoma: they both carry a mutation in the BRAF gene [42].”
- The integrated landscape of driver genomic alterations in glioblastoma (2013, methodology): “We estimated the frequencies of variant alleles in 139 paired tumor and normal whole-exome samples from TCGA using the SAVI pipeline 50 .”
- ERK/MAPK signalling pathway and tumorigenesis (2020, background): “Among the three subtypes, B-Raf has the highest mutation rate, which is 90% in melanoma (Table I) (51-73).”