Mutually exclusive extracellular signal‐regulated kinase pathway mutations are present in different stages of multi‐focal pulmonary Langerhans cell histiocytosis supporting clonal nature of the disease

Kamionek, Michal; Moghaddam, Parnian Ahmadi; Sakhdari, Ali; Kovach, Alexandra E.; Welch, Matthew; Meng, Xiuling; Dresser, Karen; Tomaszewicz, Keith; Cosar, Ediz F.; Mark, Eugene J.; Fraire, Armando E.; Hutchinson, Lloyd

doi:10.1111/his.12955

Cited by 30 publications

(21 citation statements)

References 31 publications

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“…50 Alveolar epithelium-derived GMCSF may induce av integrin expression in vivo in lung-resident monocytes, making them more susceptible to adenoviral infection. BRAF is frequently mutated in human pulmonary LCH (24%-63%) 4,8,9,[39][40][41] with much higher prevalence than KRAS (8%), 9 though NRAS mutations could be more common than KRAS.…”

Section: Discussionmentioning

confidence: 99%

“…3 Recent discoveries of somatic mutations in the genes involved in the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) pathway have unveiled that LCH pathogenesis is driven by neoplastic transformation associated with deregulated ERK pathway activation. [4][5][6][7][8][9] The BRAF T1799A mutation, leading to BRAF V600E oncoprotein expression, is most common in LCH, 4 whereas other genes in the ERK pathway, including ARAF 5 and MAP2K1, 6,7 have been also reported as mutational targets. Furthermore, NRAS 8 and KRAS 9 mutations, leading to NRAS Q61K/R and KRAS G12V/A oncoprotein expression, respectively, have been identified uniquely in pulmonary LCH cases, suggesting organ-specific contribution of oncogenic RAS to the pathogenesis of LCH.…”

Section: Introductionmentioning

confidence: 99%

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KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment

Kamata

Giblett

Pritchard

2017

Blood

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Key Points• KRAS G12D expression in mouse lung myeloid cells induces pulmonary LCH-like neoplasms.• KRAS G12D -induced LCH-like neoplasms are sensitive to in vivo treatment with 3-hydroxy-3-methylglutaryl coenzyme A inhibitor atorvastatin. -induced LCH-like mouse with the cholesterol-lowering drug atorvastatin ameliorated the pathology, implicating statins as potential therapeutics against a subset of pulmonary LCH. (Blood. 2017;130(4):514-526)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment

Kamata

Giblett

Pritchard

2017

Blood

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“…Next-generation sequencing Next-generation sequencing was performed as previously described (Kamionek et al, 2016). 37 primer pairs were used to cover the known hotspot mutations in KRAS, NRAS, HRAS (codons 12, 13, 61, and 146), BRAF (codons 460-470 and 600), and the entire coding sequence of the MAP2K1 gene.…”

Section: Patient Samplesmentioning

confidence: 99%

KRAS or BRAF mutations cause hepatic vascular cavernomas treatable with MAP2K–MAPK1 inhibition

Janardhan

Meng

Dresser

et al. 2020

Journal of Experimental Medicine

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Human hepatic vascular cavernomas, the most common benign tumor of the liver, were described in the mid-1800s, yet the mechanisms for their formation and effective treatments remain unknown. Here, we demonstrate gain-of-function mutations in KRAS or BRAF genes within liver endothelial cells as a causal mechanism for hepatic vascular cavernomas. We identified gain-of-function mutations in KRAS or BRAF genes in pathological liver tissue samples from patients with hepatic vascular cavernomas. Mice expressing these human KRASG12D or BRAFV600E mutations in hepatic endothelial cells recapitulated the human hepatic vascular cavernoma phenotype of dilated sinusoidal capillaries with defective branching patterns. KRASG12D or BRAFV600E induced “zipper-like” contiguous expression of junctional proteins at sinusoidal endothelial cell–cell contacts, switching capillaries from branching to cavernous expansion. Pharmacological or genetic inhibition of the endothelial RAS–MAPK1 signaling pathway rescued hepatic vascular cavernoma formation in endothelial KRASG12D- or BRAFV600E-expressing mice. These results uncover a major cause of hepatic vascular cavernomas and provide a road map for their personalized treatment.

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“…Similar to other forms of LCH, MAP2K1 (MEK1) mutations were observed in a subset of BRAF-wild-type PLCH lesions [69,[77][78][79]. Recently, activating NRAS Q61K/R mutations have been described in a substantial subset of PLCH lesions, whereas these mutations were only exceptionally reported in other forms of LCH (figure 5) [69].…”

Section: Pathogenesismentioning

confidence: 81%

How I manage pulmonary Langerhans cell histiocytosis

Lorillon

Tazi

2017

Eur Respir Rev

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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 BRAF V600E 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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Mutually exclusive extracellular signal‐regulated kinase pathway mutations are present in different stages of multi‐focal pulmonary Langerhans cell histiocytosis supporting clonal nature of the disease

Cited by 30 publications

References 31 publications

KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment

KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment

KRAS or BRAF mutations cause hepatic vascular cavernomas treatable with MAP2K–MAPK1 inhibition

How I manage pulmonary Langerhans cell histiocytosis

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