دورية أكاديمية
MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis.
| العنوان: | MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis. |
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| المؤلفون: | Nelson DS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., van Halteren A, Quispel WT, van den Bos C, Bovée JV, Patel B, Badalian-Very G, van Hummelen P, Ducar M, Lin L, MacConaill LE, Egeler RM, Rollins BJ |
| المصدر: | Genes, chromosomes & cancer [Genes Chromosomes Cancer] 2015 Jun; Vol. 54 (6), pp. 361-8. Date of Electronic Publication: 2015 Mar 31. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley-Liss Country of Publication: United States NLM ID: 9007329 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-2264 (Electronic) Linking ISSN: 10452257 NLM ISO Abbreviation: Genes Chromosomes Cancer Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: New York, NY : Wiley-Liss Original Publication: New York : A.R. Liss, c1989- |
| مواضيع طبية MeSH: | Mutation*, Histiocytosis, Langerhans-Cell/*genetics , MAP Kinase Kinase 1/*genetics , MAP Kinase Kinase Kinase 1/*genetics, Antineoplastic Agents/pharmacology ; Humans ; MAP Kinase Kinase 1/metabolism ; MAP Kinase Kinase Kinase 1/metabolism ; Phosphorylation/drug effects ; Pyridones/pharmacology ; Pyrimidinones/pharmacology ; Signal Transduction |
| مستخلص: | Langerhans cell histiocytosis (LCH) is now understood to be a neoplastic disease in which over 50% of cases have somatic activating mutations of BRAF. However, the extracellular signal-related (ERK) pathway is activated in all cases including those with wild type BRAF alleles. Here, we applied a targeted massively parallel sequencing panel to 30 LCH samples to test for the presence of additional genetic alterations that might cause ERK pathway activation. In 20 BRAF wild type samples, we found 3 somatic mutations in MAP2K1 (MEK1) including C121S and C121S/G128D in the kinase domain, and 56_61QKQKVG>R, an in-frame deletion in the N-terminal regulatory domain. All three variant proteins constitutively phosphorylated ERK in in vitro kinase assays. The C121S/G128D and 56_61QKQKVG>R variants were resistant to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib in vitro. Within the entire sample set, we found 3 specimens with mutations in MAP3K1 (MEKK1), including two truncation mutants, T779fs and T1481fs; T1481fs encoded an unstable and nonfunctional protein when expressed in vitro. T779fs was present in a specimen carrying BRAF V600E. The third variant was a single nucleotide substitution, E1286V, which was fully functional and is likely a germline polymorphism. These results indicate that LCH cells can harbor additional genetic alterations in the RAS-RAF-MEK pathway which, in the case of MAP2K1, may be responsible for ERK activation in a wild type BRAF setting. The resistance of some of these variants to trametinib may also have clinical implications for the combined use of RAF and MEK inhibitors in LCH. (© 2015 Wiley Periodicals, Inc.) |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Pyridones) 0 (Pyrimidinones) 33E86K87QN (trametinib) EC 2.7.11.25 (MAP Kinase Kinase Kinase 1) EC 2.7.11.25 (MAP3K1 protein, human) EC 2.7.12.2 (MAP Kinase Kinase 1) EC 2.7.12.2 (MAP2K1 protein, human) |
| تواريخ الأحداث: | Date Created: 20150423 Date Completed: 20151029 Latest Revision: 20220331 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1002/gcc.22247 |
| PMID: | 25899310 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1098-2264 |
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| DOI: | 10.1002/gcc.22247 |