scholarly journals RecurrentNRASmutations in pulmonary Langerhans cell histiocytosis

2016 ◽  
Vol 47 (6) ◽  
pp. 1785-1796 ◽  
Author(s):  
Samia Mourah ◽  
Alexandre How-Kit ◽  
Véronique Meignin ◽  
Dominique Gossot ◽  
Gwenaël Lorillon ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Lung Tissue ◽  
Langerhans Cell Histiocytosis ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Univariate Analysis ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Normal Lung ◽  
Pulmonary Langerhans Cell Histiocytosis

The mitogen-activated protein kinase (MAPK) pathway is constantly activated in Langerhans cell histiocytosis (LCH). Mutations of the downstream kinasesBRAFandMAP2K1mediate this activation in a subset of LCH lesions. In this study, we attempted to identify other mutations which may explain the MAPK activation in nonmutatedBRAFandMAP2K1LCH lesions.We analysed 26 pulmonary and 37 nonpulmonary LCH lesions for the presence ofBRAF,MAP2K1,NRASandKRASmutations. Grossly normal lung tissue from 10 smoker patients was used as control. Patient spontaneous outcomes were concurrently assessed.BRAFV600Emutations were observed in 50% and 38% of the pulmonary and nonpulmonary LCH lesions, respectively. 40% of pulmonary LCH lesions harbouredNRASQ61K/Rmutations, whereas noNRASmutations were identified in nonpulmonary LCH biopsies or in lung tissue control. In seven out of 11NRASQ61K/R-mutated pulmonary LCH lesions,BRAFV600Emutations were also present. Separately genotyping each CD1a-positive area from the same pulmonary LCH lesion demonstrated that these concurrentBRAFandNRASmutations were carried by different cell clones.NRASQ61K/Rmutations activated both the MAPK and AKT (protein kinase B) pathways. In the univariate analysis, the presence of concurrentBRAFV600EandNRASQ61K/Rmutations was significantly associated with patient outcome.These findings highlight the importance ofNRASgenotyping of pulmonary LCH lesions because the use of BRAF inhibitors in this context may lead to paradoxical disease progression. These patients might benefit from MAPK kinase inhibitor-based treatments.

scholarly journals How I manage pulmonary Langerhans cell histiocytosis

2017 ◽  
Vol 26 (145) ◽  
pp. 170070 ◽  
Author(s):  
Gwenaël Lorillon ◽  
Abdellatif Tazi
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Mapk Pathway ◽  
Therapeutic Option ◽  
Significant Proportion ◽  
Airflow Obstruction ◽  
Forced Expiratory Volume ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Pulmonary Langerhans Cell Histiocytosis ◽  
Right Heart Catheterisation

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare sporadic cystic lung disease of unknown aetiology that is characterised by the infiltration and destruction of the wall of distal bronchioles by CD1a+Langerhans-like cells. In adults, PLCH is frequently isolated and affects young smokers of both sexes. Recent multicentre studies have led to the more standardised management of patients in clinical practice. Smoking cessation is essential and is occasionally the only suitable intervention. Serial lung function testing is important because a significant proportion of patients may experience an early decline in forced expiratory volume in 1 s and develop airflow obstruction. Cladribine was reported to dramatically improve progressive PLCH in some patients. Its efficacy and tolerance are currently being evaluated. Patients who complain of unexplained dyspnoea with decreased diffusing capacity of the lung for carbon monoxide should be screened for pulmonary hypertension by Doppler echocardiography, which must be confirmed by right heart catheterisation. Lung transplantation is a therapeutic option for patients with advanced PLCH.The identification of theBRAFV600Emutation in approximately half of Langerhans cell histiocytosis lesions, including PLCH, and other mutations of the mitogen-activated protein kinase (MAPK) pathway in a subset of lesions has led to targeted treatments (BRAF and MEK (MAPK kinase) inhibitors). These treatments need to be rigorously evaluated because of their potentially severe side-effects.

scholarly journals Ghrelin exerts a proliferative effect on a rat pituitary somatotroph cell line via the mitogen-activated protein kinase pathway

2004 ◽  
pp. 233-240 ◽  
Author(s):  
AM Nanzer ◽  
S Khalaf ◽  
AM Mozid ◽  
RC Fowkes ◽  
MV Patel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Cell Line ◽  
Kinase Inhibitor ◽  
Thymidine Incorporation ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Gh3 Cells ◽  
Rat Pituitary ◽  
Mitogen Activated Protein

OBJECTIVES: Ghrelin is a brain-gut peptide with GH-releasing and appetite-inducing activities and a widespread tissue distribution. Ghrelin is the endogenous ligand of the GH secretagogue receptor type 1a (GHS-R1a), and both ghrelin and the GHS-R1a are expressed in the pituitary. There are conflicting data regarding the effects of ghrelin on cell proliferation. A positive effect on proliferation and activation of the mitogen-activated protein kinase (MAPK) pathway has been found in hepatoma, adipose, cardiomyocyte and prostate cell lines. However, ghrelin has also been shown to have anti-proliferative effects on breast, lung and thyroid cell lines. We therefore examined the effect of ghrelin on the rat pituitary cell line GH3. METHODS: RT-PCR was used for the detection of GHS-R1a and pre-proghrelin mRNA expression in GH3 cells. The effect of ghrelin on cell proliferation was studied using [(3)H]thymidine incorporation; cell counting and the activation of the MAPK pathway were studied using immunoblotting and inhibitors of the extracellular signal-regulated kinase 1 and 2 (ERK 1/2), protein kinase C (PKC) and tyrosine phosphatase pathways. RESULTS: GHS-R1a and ghrelin mRNA expression were detected in GH3 cells. Ghrelin, at 10(-10) to 10(-6) M concentrations, significantly increased [(3)H]thymidine incorporation (at 10(-9) M, 183+/-13% (means+/-s.e.m.) compared with untreated controls), while 12-phorbol 13-myristate acetate (PMA) at 10(-7) M (used as a positive control) caused a 212+/-14% increase. A reproducible stimulatory effect of desoctanoyl ghrelin was also observed on [(3)H]thymidine incorporation (135+/-5%; P<0.01 at 10(-9) M compared with control), as well as on the cell count (control 6.8 x 10(4)+/-8.7 x 10(3) cells/ml vs desoctanoyl ghrelin (10(-9) M) 1.04 x 10(5)+/-7.5 x 10(3) cells/ml; P<0.01). Ghrelin caused a significant increase in phosphorylated ERK 1/2 in immunoblotting, while desoctanoyl ghrelin showed a smaller but also significant stimulatory effect. The positive effect of ghrelin and desoctanoyl ghrelin on [(3)H]thymidine incorporation was abolished by the MAPK kinase inhibitor U0126, the PKC inhibitor GF109203X and the tyrosine kinase inhibitor tyrphostin 23, suggesting that the ghrelin-induced cell proliferation of GH3 cells is mediated both via a PKC-MAPK-dependent pathway and via a tyrosine kinase-dependent pathway. This could also be clearly demonstrated by Western blot analysis, where a transient increase in ERK 1/2 phosphorylation by ghrelin was attenuated by all three inhibitors. CONCLUSION: We have shown a novel role for ghrelin in stimulating the proliferation of a somatotroph pituitary tumour cell line, suggesting that ERK activation is involved in mediating the effects of ghrelin on cell proliferation. Desoctanoyl ghrelin showed a similar effect. As ghrelin has been shown to be expressed in both normal and adenomatous pituitary tissue, locally produced ghrelin may play a role in pituitary tumorigenesis via an autocrine/paracrine pathway.

Pulmonary Langerhans Cell Histiocytosis

2020 ◽  
Vol 41 (02) ◽  
pp. 269-279
Author(s):  
Brian Shaw ◽  
Michael Borchers ◽  
Dani Zander ◽  
Nishant Gupta
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Treatment Options ◽  
Skin Lesions ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Myeloid Neoplasm ◽  
Cystic Lung ◽  
Pulmonary Langerhans Cell Histiocytosis ◽  
Mitogen Activated Protein ◽  
The Central Nervous System

AbstractPulmonary Langerhans cell histiocytosis (PLCH) is a diffuse cystic lung disease that is strongly associated with exposure to cigarette smoke. Recently, activating pathogenic mutations in the mitogen-activated protein kinase pathway have been described in the dendritic cells in patients with PLCH and have firmly established PLCH to be an inflammatory myeloid neoplasm. Disease course and prognosis in PLCH are highly variable among individual patients, ranging from spontaneous resolution to development of pulmonary hypertension and progression to terminal respiratory failure. A subset of patients with PLCH may have extrapulmonary involvement, typically involving the skeletal system in the form of lytic lesions, skin lesions, or the central nervous system most commonly manifesting in the form of diabetes insipidus. Smoking cessation is the cornerstone of treatment in patients with PLCH and can lead to disease regression or stabilization in a substantial proportion of patients. Further insight into the underlying molecular pathogenesis of PLCH has paved the way for the future development of disease-specific biomarkers and targeted treatment options directed against the central disease-driving mutations.

Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies

2008 ◽  
Vol 413 (3) ◽  
pp. 429-436 ◽  
Author(s):  
Yan Zeng ◽  
Heidi Sankala ◽  
Xiaoxiao Zhang ◽  
Paul R. Graves
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Phosphorylation Site ◽  
Mitogen Activated Protein Kinase ◽  
Processing Bodies ◽  
Mitogen Activated Protein

Ago (Argonaute) proteins are essential effectors of RNA-mediated gene silencing. To explore potential regulatory mechanisms for Ago proteins, we examined the phosphorylation of human Ago2. We identified serine-387 as the major Ago2 phosphorylation site in vivo. Phosphorylation of Ago2 at serine-387 was significantly induced by treatment with sodium arsenite or anisomycin, and arsenite-induced phosphorylation was inhibited by a p38 MAPK (mitogen-activated protein kinase) inhibitor, but not by inhibitors of JNK (c-Jun N-terminal kinase) or MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase]. MAPKAPK2 (MAPK-activated protein kinase-2) phosphorylated bacterially expressed full-length human Ago2 at serine-387 in vitro, but not the S387A mutant. Finally, mutation of serine-387 to an alanine residue or treatment of cells with a p38 MAPK inhibitor reduced the localization of Ago2 to processing bodies. These results suggest a potential regulatory mechanism for RNA silencing acting through Ago2 serine-387 phosphorylation mediated by the p38 MAPK pathway.

Transcriptomic Landscape of Circulating Mononuclear Phagocytes in Langerhans Cell Histiocytosis at Single-cell Level

Blood ◽  
2021 ◽  
Author(s):  
Hui Shi ◽  
Han He ◽  
Lei Cui ◽  
Egle Kvedaraite ◽  
Zhilei Bian ◽  
...  
Keyword(s):  
Single Cell ◽  
Langerhans Cell Histiocytosis ◽  
Mapk Pathway ◽  
Braf Inhibitor ◽  
Clinical Diagnostics ◽  
Langerhans Cell ◽  
Mononuclear Phagocytes ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm caused by aberrant activation of the mitogen-activated protein kinase (MAPK) pathway. Circulating myeloid cells from patients often carry disease-associated mutations and can be differentiated into langerinhigh LCH-like cells in vitro, but their detailed immune-phenotypic and molecular profiles are lacking and could shed key insights into disease biology. Here we recruited 217 pediatric LCH patients and took blood and tissue samples for BRAFV600E analysis. Immune-phenotyping of the circulating Lin-HLA-DR+ immune population in 49 of these patients revealed that decreased frequency of pDC was significantly linked to disease severity. By single-cell RNA sequencing of samples from 14 patients, we identified key changes in expression of RAS-MAPK-ERK signaling-related genes and transcription factors in distinct members of the mononuclear phagocyte system in the presence of BRAFV600E. Moreover, treatment of patients with the BRAF inhibitor Dabrafenib resulted in MAPK cascade inhibition, inflammation prevention, and regulation of cellular metabolism within mononuclear phagocytes. Finally, we also observed elevated expression of RAS-MAPK-ERK signaling-related genes in a CD207+CD1a+ cell subcluster in skin. Taken together, our data extends the molecular understanding of LCH biology at single-cell resolution, which might contribute to improvement of clinical diagnostics and therapeutics, and aid in the development of personalized medicine approaches.

scholarly journals Results of TETimaX Trial of Langerhans Cell Histiocytosis Treatment and Perspectives on the Role of Imatinib Mesylate in the Era of MAPK Signaling

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1759
Author(s):  
Liliana Montella ◽  
Margaret Ottaviano ◽  
Vittorio Riccio ◽  
Fernanda Picozzi ◽  
Gaetano Facchini ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Langerhans Cell Histiocytosis ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Mapk Signaling ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRβ expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRβ was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age.

scholarly journals Creating and Testing a CD207+ Langerhans Cell Histiocytosis-like Cell Line

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5399-5399
Author(s):  
Jessica Velazquez ◽  
Amel Sengal ◽  
Carl E. Allen ◽  
Rikhia Chakraborty
Keyword(s):  
Cell Line ◽  
Langerhans Cell Histiocytosis ◽  
Conflicts Of Interest ◽  
Mapk Pathway ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Established Cell Line ◽  
Human Telomerase Reverse Transcriptase ◽  
Cytokine Cocktail ◽  
Immortalized Cells

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by pathological CD207+ dendritic cells (DCs) with persistent mitogen-activated protein kinase (MAPK) activation. Investigations into LCH have historically been challenged by the small percentage of pathologic CD207+ DCs. No cell lines with morphology or function representing LCH lesion CD207+ DCs currently exist. We utilized four strategies to generate cell line(s) mimicking differentiated LCH pathogenic cells. First, CD207+ cells were isolated from the lesion of an LCH patient and cultured in a cytokine cocktail. The cells maintained CD1a and CD207 expression for two weeks, after which there were significant changes in cell morphology and progression to cell death. When a similar approach was implemented to isolate and culture skin CD207+ cells, the cells were viable for only three days, supporting the potential role for somatic activating MAPK mutations in LCH lesion DCs to prolong viability. CD207+ cells were then isolated from HLA-DR+ (lineage negative) cells from the lymphoid stroma of healthy tonsils (tCD207+). The tCD207+ cells were transduced with a lentivirus encoding human telomerase reverse transcriptase (hTERT). These cells, also lacking MAPK activating mutations, died two weeks post-transduction. A fourth approach has been more successful in which tCD207+ cells were cultured in a cytokine cocktail which provided MAPK pathway stimulation. The cells retained CD207 expression and survived in culture for over two weeks. The cells were then immortalized using a lentivirus encoding HOXA9. Immortalized cells maintained CD207 expression. Allele specific MAPK pathway mutations (BRAF and MAP2K1) are being generated by class II CRISPR/Cpf1 genome editing as Cpf1 has been shown to have robust activity to induce specific disruption of only mutant, but not wild-type, BRAF allele. The phenotypic and genomic characteristics of the immortalized cells expressing the different MAPK pathway mutations will be assessed by RHG-banding cytogenetic analysis, fluorescence in situ hybridization, gene expression analysis, and immuno‐cytochemistry and results will be compared to cells isolated from LCH lesions to confirm whether the established cell line may be a viable in vitro mimic of the LCH lesion DC. Disclosures No relevant conflicts of interest to declare.

scholarly journals RAF/MEK/extracellular signal–related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions

2017 ◽  
Vol 215 (1) ◽  
pp. 319-336 ◽  
Author(s):  
Brandon Hogstad ◽  
Marie-Luise Berres ◽  
Rikhia Chakraborty ◽  
Jun Tang ◽  
Camille Bigenwald ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Langerhans Cell Histiocytosis ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Phagocytic Cells ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Myeloid Neoplasia

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAFV600E mutations localizing to CD207+ DCs within lesions. However, the mechanisms driving BRAFV600E+ LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal–related kinase activity induced by BRAFV600E inhibits C-C motif chemokine receptor 7 (CCR7)–mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAFV600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death.

Mechanisms of Resistance to Mitogen-Activated Protein Kinase Pathway Inhibition in BRAF-Mutant Melanoma

2012 ◽  
pp. 680-684 ◽  
Author(s):  
Eva M. Goetz ◽  
Levi A. Garraway
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Drug Binding ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Mechanisms Of Resistance ◽  
Mitogen Activated Protein

Overview: Anticancer drug resistance remains a crucial impediment to the care of many patients with cancer. Although the exact mechanisms of resistance may differ for each therapy, common mechanisms of resistance predominate, including drug inactivation or modification, mutation of the target protein, reduced drug accumulation, or bypass of target inhibition. With the discovery and use of targeted therapies (such as small-molecule kinase inhibitors), resistance has received renewed attention—especially in light of the dramatic responses that may emerge from such therapeutics in particular genetic or molecular contexts. Recently, the mitogen-activated protein kinase (MAPK) pathway has become exemplary in this regard, since it is activated in many different cancers. Drugs targeting RAF and MAPK kinase (MEK) are currently in clinical trials for the treatment of several types of cancer. Vemurafenib, a selective RAF kinase inhibitor recently approved for the treatment of BRAF(V600E) melanoma, shows strong efficacy initially; however, the development of resistance is nearly ubiquitous. In vitro testing and analysis of patient samples have uncovered several mechanisms of resistance to RAF inhibition. Surprisingly, mutations in the drug-binding pocket have not thus far been observed; however, other alterations at the level of RAF, as well as downstream activation of MEK and bypass of MEK/extracellular signal-regulated kinase (ERK) signaling altogether, confer resistance to vemurafenib. Looking forward, combined RAF and MEK inhibitor treatments may improve efficacy—yet we must anticipate mechanisms of resistance to this combination as well. Therefore, understanding and/or determining the mechanism of resistance are paramount to effective cancer treatment.

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