Abstract
Langerhans cell histiocytosis (LCH) is characterized by the accumulation of Langerin (CD207)-expressing histiocytes. Mutational activation of mitogen-activated protein kinase pathway genes, in particular BRAF, drives most cases. To test whether activated BRAF is sufficient for the development of LCH, we engineered mice to express BRAF V600E under the control of the human Langerin promoter. These mice have shortened survivals, smaller lymphoid organs, absent Leydig cells, and fewer epidermal LCs than controls, but do not accumulate histiocytes. To test whether the absence of histiocyte proliferation could be due to oncogene-induced senescence, we engineered homozygous Pten loss in the same cells that expressed BRAF V600E. Like mice with intact Pten, these mice have shortened survivals, smaller thymi, and absent Leydig cells. However, loss of Pten also leads to the accumulation of CD207+ histiocytes in spleen, thymus, and some lymph nodes. While many CD207+ histiocytes in the thymus are CD8-, reminiscent of LCH cells, the CD207+ histiocytes in the spleen and lymph nodes are CD8+. These mice also accumulate large numbers of CD207- cells in the lamina propria (LP) of the small intestine. Both the lymphoid and LP phenotypes are likely due to human Langerin promoter-driven BRAF V600E expression in resident CD8+ dendritic cells in the former and LP dendritic cells in the latter and confirm that Pten loss is required to overcome inhibitory pathways induced by BRAF V600E expression. The complex phenotype of these mice is a consequence of the multiple murine cell types in which the human Langerin promoter is active.
Highlights
Langerhans cell histiocytosis (LCH) is a rare disease characterized by the accumulation of histiocytes having features reminiscent of Langerhans cells [1]
BRAF V600E expression and Pten loss in murine histiocytosis of childhood, LCH can occur at any age and has a broad spectrum of clinical behaviors ranging from a mild, self-limited disease to an aggressive multi-system disorder with significant mortality
To test the effect of BRAF V600E expression in Langerin-expressing cells in vivo we crossed mice carrying the conditional BRAF allele, Braf CA, with mice carrying a bacterial artificial chromosome in which the human Langerin locus was modified by inserting a cDNA encoding cre recombinase at the translation initiation site (Tg(CD207-cre))
Summary
Langerhans cell histiocytosis (LCH) is a rare disease characterized by the accumulation of histiocytes having features reminiscent of Langerhans cells [1]. The essential “driver” role for these abnormalities in LCH has been proven by the remarkable clinical responses seen in patients with BRAF or MAP2K1 mutations who are treated with RAF or MEK inhibitors [6,7,8] While these observations have advanced our understanding of LCH and provided new therapeutic targets, they have led to new questions. LCH samples with mutations that activate the MAP kinase pathway only rarely have additional mutations in genes that drive other pathways This observation suggests two alternative possibilities: either LCH precursor cells are uniquely able to accommodate a powerful dominant oncogene and respond by proliferating or, like other cells, they require inactivation of a senescence pathway which has not yet been identified. The lack of LCH precursor cell lines makes this a daunting question to answer
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