MAP2K1 and MAP3K1 mutations in langerhans cell histiocytosis

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, In

Somatic activating ARAF mutations in Langerhans cell histiocytosis

The extracellular signal-regulated kinase (ERK) signaling pathway is activated in Langerhans cell histiocytosis (LCH) histiocytes, but only 60% of cases carry somatic activating mutations of BRAF. To identify other genetic causes of ERK pathway activation, we performed whole exome sequencing on purified LCH cells in 3 cases. One patient with wild-type BRAF alleles in his histiocytes had compound mutations in the kinase domain of ARAF. Unlike wild-type ARAF, this mutant was a highly active mitogen-activated protein kinase kinase in vitro and was capable of transforming mouse embryo fibroblasts. Mutant ARAF activity was inhibited by vemurafenib, a BRAF inhibitor, indicating the importance of fully evaluating ERK pathway abnormalities in selecting LCH patients for targeted inhibitor therap

MAP2K1 and MAP3K1 mutations in langerhans cell histiocytosis

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, In

UCI Rocket Project

The UCI Rocket Project is an undergraduate engineering design team at the University of California, Irvine, dedicated to the design and development of liquid bi-propellant rockets. The team’s main goal is to design a liquid rocket capable of reaching 100 km for the Base11 Space Challenge. The current iteration of the rocket is designed to reach 45,000 ft as a preliminary verification of the team’s design and manufacturing capabilities. The design utilizes a pressure fed system with a propellant combination of liquid methane and liquid oxygen. As the team moves further into the testing and verification stages, development of the rocket capable of reaching 100 km begins. There are a total of four launch windows for the Base11 competition that begin in May 2020 and end in December 2021. The team has a dedicated lab space with the resources necessary for general design and assembly, but manufacturing is typically contracted to professional companies. As the space industry continues to grow, the UCI Rocket Project will continue giving undergraduate students relevant and impactful hands-on experience to prepare them for the challenges of working in the industry.Advisors: Professor Mark WalterProfessor Ken Meas

UCI Rocket Project

The UCI Rocket Project is an undergraduate engineering design team at the University of California, Irvine, dedicated to the design and development of liquid bi-propellant rockets. The team’s main goal is to design a liquid rocket capable of reaching 100 km for the Base11 Space Challenge. The current iteration of the rocket is designed to reach 45,000 ft as a preliminary verification of the team’s design and manufacturing capabilities. The design utilizes a pressure fed system with a propellant combination of liquid methane and liquid oxygen. As the team moves further into the testing and verification stages, development of the rocket capable of reaching 100 km begins. There are a total of four launch windows for the Base11 competition that begin in May 2020 and end in December 2021. The team has a dedicated lab space with the resources necessary for general design and assembly, but manufacturing is typically contracted to professional companies. As the space industry continues to grow, the UCI Rocket Project will continue giving undergraduate students relevant and impactful hands-on experience to prepare them for the challenges of working in the industry.Advisors: Professor Mark WalterProfessor Ken Meas