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

Abstract：

:Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm associated with somatic mutations in the genes involved in the RAF/MEK/extracellular signal-regulated kinase (ERK) signaling pathway. Recently, oncogenic mutations in NRAS/KRAS, upstream regulators of the RAF/MEK/ERK pathway, have been reported in pulmonary, but not in nonpulmonary, LCH cases, suggesting organ-specific contribution of oncogenic RAS to LCH pathogenesis. Using a mouse model expressing KRASG12D in the lung by nasal delivery of adenoviral Cre recombinase (Cre), here we show that KRASG12D expression in lung-resident myeloid cells induces pulmonary LCH-like neoplasms composed of pathogenic CD11chighF4/80+CD207+ cells. The pathogenic cells were mitotically inactive, but proliferating precursors were detected in primary cultures of lung tissue. These precursors were derived, at least in part, from CD11cdimCD11bintGr1- lung-resident monocytic cells transformed by KRASG12D In contrast, BRAFV600E expression induced by the same method failed to develop LCH-like neoplasms, suggesting that each oncogene may initiate pulmonary LCH by transforming different types of lung-resident myeloid cells. In vivo treatment of the KRASG12D-induced LCH-like mouse with the cholesterol-lowering drug atorvastatin ameliorated the pathology, implicating statins as potential therapeutics against a subset of pulmonary LCH.

journal_name

Blood

journal_title

Blood

authors

Kamata T,Giblett S,Pritchard C

doi

10.1182/blood-2017-02-770149

subject

Has Abstract

pub_date

2017-07-27 00:00:00

pages

514-526

issue

4

eissn

0006-4971

issn

1528-0020

pii

blood-2017-02-770149

journal_volume

130

pub_type

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