Oncogene-induced senescence distinguishes indolent from aggressive forms of pulmonary and non-pulmonary Langerhans cell histiocytosis.
The clonal/neoplastic nature of Langerhans cell histiocytosis (LCH) has recently been demonstrated by a high prevalence of BRAF mutations, including pulmonary LCH (PLCH). We hypothesized that BRAF-induced senescence, as demonstrated in nevi and melanoma, is involved in the pathogenesis of LCH and PLCH. In a series of pulmonary (19 cases) and non-pulmonary LCH (19 cases), including five aggressive cases, we investigated occurrence of the BRAF V600E mutation by molecular analysis and/or immunohistochemistry using a validated antibody (VE1). The expression of cell-senescence markers p16(INK4a) and p21(CIP1/WAF1) was also immunohistochemically investigated. We demonstrated that 6/19 cases of LCH and 12/19 cases of PLCH were VE1 positive, matching with molecular analysis, and in all cases both p16(INK4a) and p21(CIP1/WAF1) were expressed, irrespective of BRAF mutation status. Interestingly, all the aggressive cases did not express p16(INK4a), thus suggesting that loss of senescence control could be related to clinical aggressiveness of LCH, as in melanoma.
Department of Pathology and Diagnostics, University of Verona , Verona , Italy.
Marco
M
Chilosi
Fabio
F
Facchetti
Anna
A
Caliò
Alberto
A
Zamò
Matteo
M
Brunelli
Guido
G
Martignoni
Andrea
A
Rossi
Licia
L
Montagna
Paola
P
Piccoli
Alessandra
A
Dubini
Andrea
A
Tironi
Sara
S
Tomassetti
Venerino
V
Poletti
Claudio
C
Doglioni
D000293:Adolescent; D000328:Adult; D000368:Aged; D016922:Cellular Senescence / Q000235:genetics*; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D006646:Histiocytosis, Langerhans-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D048493:Proto-Oncogene Proteins B-raf
BRAF mutation; PLCH; p16INK4a; p21CIP1/WAF1; senescence in LCH