BRAFV 600E or mutant MAP2K1 human CD34+ cells establish Langerhans cell-like histiocytosis in immune-deficient mice.
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ABSTRACT:
SUBMITTER: Rafiei A
PROVIDER: S-EPMC7556147 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
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BRAFV 600E or mutant MAP2K1 human CD34+ cells establish Langerhans cell-like histiocytosis in immune-deficient mice.
Rafiei Anahita A Wilk C Matthias CM Helbling Patrick M PM Myburgh Renier R Saito Yasuyuki Y Haralambieva Eugenia E Soldini Davide D Chakraborty Rikhia R Merad Miriam M Allen Carl E CE Nombela-Arrieta Cesar C Manz Markus G MG
Blood advances 20201001 19
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Project description:We describe a xenograft model for human LCH-like disease in which we transduced human Cord Blood CD34+ HSPCs with a virus coding for BRAF-V600E - the most abundant pathognomonic somatic mutation occuiring in LCH. Cells were subsequently subjected to RNA-sequencing or transplanted into humanized MISTRG or NSG mice.
2020-10-12 | GSE153831 | GEO
Project description:BRAFV600E or mutant MAP2K1 human CD34+ cells establish Langerhans cell-like histiocytosis in immunodeficient mice
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Project description:BackgroundLangerhans cell histiocytosis (LCH) features inflammatory granuloma characterised by the presence of CD1a+ dendritic cells or 'LCH cells'. Badalian-Very et al. recently reported the presence of a canonical (V600E)B-RAF mutation in 57% of paraffin-embedded biopsies from LCH granuloma. Here we confirm their findings and report the identification of two novel B-RAF mutations detected in LCH patients.Methods and resultsMutations of B-RAF were observed in granuloma samples from 11 out of 16 patients using 'next generation' pyrosequencing. In 9 cases the mutation identified was (V600E)B-RAF. In 2 cases novel polymorphisms were identified. A somatic (600DLAT)B-RAF insertion mimicked the structural and functional consequences of the (V600E)B-RAF mutant. It destabilized the inactive conformation of the B-RAF kinase and resulted in increased ERK activation in 293 T cells. The (600DLAT)B-RAF and (V600E)B-RAF mutations were found enriched in DNA and mRNA from the CD1a+ fraction of granuloma. They were absent from the blood and monocytes of 58 LCH patients, with a lower threshold of sequencing sensitivity of 1%-2% relative mutation abundance. A novel germ line (T599A)B-RAF mutant allele was detected in one patient, at a relative mutation abundance close to 50% in the LCH granuloma, blood monocytes and lymphocytes. However, (T599A)B-RAF did not destabilize the inactive conformation of the B-RAF kinase, and did not induce increased ERK phosphorylation or C-RAF transactivation.ConclusionsOur data confirmed presence of the (V600E)B-RAF mutation in LCH granuloma of some patients, and identify two novel B-RAF mutations. They indicate that (V600E)B-RAF and (600DLAT)B-RAF mutations are somatic mutants enriched in LCH CD1a(+) cells and absent from the patient blood. Further studies are needed to assess the functional consequences of the germ-line (T599A)B-RAF allele.
| S-EPMC3323620 | biostudies-literature
Project description:Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.
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Project description:Pulmonary Langerhans cell (LC) histiocytosis (PLCH) has unknown cause and is a rare neoplastic disorder characterized by the infiltration of lungs and various organs by bone marrow-derived Langerhans cells with an accompanying strong inflammatory response. These cells carry somatic mutations of BRAF gene and/or NRAS, KRAS, and MAP2K1 genes, which cause activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. PLCH occurs predominantly in young smokers, without gender predominance. Lungs might be involved as an isolated organ or as part of a multiorgan disease. High-resolution computed chest tomography plays an outstanding role in PLCH diagnosis. The typical radiological picture of PLCH is the presence of small intralobular nodules, "tree in bud" opacities, cavitated nodules, and thin- and thick-walled cysts, frequently confluent. Histological examination of the lesion and demonstration of characteristic eosinophilic granulomas with the presence of LCs that display antigen CD1a or CD207 in immunohistochemistry are required for definite diagnosis. Smoking cessation is the most important recommendation for PLCH patients, but treatment of progressive PLCH and multisystem disease is based on chemotherapy. Recently, new targeted therapies have been implemented.
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Project description:The inflammation/immune response pathway is considered a key contributor to the development of Langerhans cell histiocytosis (LCH) bone metastasis. However, the dynamic changes in the immune microenvironment of LCH bone metastasis and critical regulators are still unclear. Expression profiling by arrays of GSE16395, GSE35340, and GSE122476 was applied to detect the immune microenvironment changes in the development of LCH bone metastasis. The single-cell high-throughput sequencing of GSE133704, involved in LCH bone lesions, was analyzed. The online database Metascape and gene set variation analysis (GSVA) algorithms were used to detect the gene function of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein-protein interaction (PPI) network of hub regulators was constructed by the STRING database. In these results, key immune cells, such as Tem cells, NK T cells, CD8(+) T cells, and Th1 cells, were identified in LCH bone metastasis. These genes, which include LAG3, TSPAN5, LPAR5, VEGFA, CXCL16, CD74, and MARCKS, may significantly correlate with the cellular infiltration of B cells, aDCs, pDCs, cytotoxic cells, T cells, CD8+ T cells, T helper cells, and Tcm cells. In conclusion, our study constructed an atlas of the immune microenvironment of LCH bone metastasis. Genes including LAG3, TSPAN5, LPAR5, VEGFA, CXCL16, CD74, and MARCKS may be involved in the development of LCH bone metastasis. The hub gene-immune cell interactive map may be a potential prognostic biomarker for the progression of LCH bone metastasis and synergetic targets for immunotherapy in LCH patients.
| S-EPMC9879691 | biostudies-literature
Project description:Nonhuman primates (NHPs) represent one of the most important models for preclinical studies of novel biomedical interventions. In contrast with small animal models, however, widespread utilization of NHPs is restricted by cost, logistics, and availability. Therefore, we sought to develop a translational primatized mouse model, akin to a humanized mouse, to allow for high-throughput in vivo experimentation leveraged to inform large animal immunology-based studies. We found that adult rhesus macaque mobilized blood (AMb) CD34+-enriched hematopoietic stem and progenitor cells (HSPCs) engrafted at low but persistent levels in immune-deficient mice harboring transgenes for human (NHP cross-reactive) GM-CSF and IL3, but did not in mice with wild-type murine cytokines lacking NHP cross-reactivity. To enhance engraftment, fetal liver-derived HSPCs were selected as the infusion product based on an increased CD34hi fraction compared with AMb and bone marrow. Coupled with cotransplantation of rhesus fetal thymic fragments beneath the mouse kidney capsule, fetal liver-derived HSPC infusion in cytokine-transgenic mice yielded robust multilineage lymphohematopoietic engraftment. The emergent immune system recapitulated that of the fetal monkey, with similar relative frequencies of lymphocyte, granulocyte, and monocyte subsets within the thymic, secondary lymphoid, and peripheral compartments. Importantly, while exhibiting a predominantly naïve phenotype, in vitro functional assays demonstrated robust cellular activation in response to nonspecific and allogenic stimuli. This primatized mouse represents a viable and translatable model for the study of hematopoietic stem cell physiology, immune development, and functional immunology in NHPs. Summary Sentence: Engraftment of rhesus macaque hematopoietic tissues in immune-deficient mice yields a robust BLT/NeoThy-type primatized mouse model for studying nonhuman primate hematopoiesis and immune function in vivo.
| S-EPMC9522924 | biostudies-literature
Project description: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 the BRAFV600E mutation 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.
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