BRAF V600E and Pten deletion in mice produces a histiocytic disorder with features of Langerhans cell histiocytosis


Autoři: David S. Nelson aff001;  Ryan L. Marano aff001;  Yechaan Joo aff001;  Sara Y. Tian aff001;  Bhumi Patel aff001;  Daniel H. Kaplan aff002;  Mark J. Shlomchik aff002;  Kristen Stevenson aff004;  Roderick T. Bronson aff005;  Barrett J. Rollins aff001
Působiště autorů: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States of America aff001;  Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America aff002;  Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America aff003;  Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, United States of America aff004;  Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, United States of America aff005;  Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222400

Souhrn

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.

Klíčová slova:

Biology and life sciences – Physiology – Spleen – Thymus – Histiocytes – Antigen-presenting cells – Dendritic cells – Langerhans cells – Cell biology – Cellular types – Animal cells – Blood cells – White blood cells – Immune cells – Precursor cells – Molecular biology – Molecular biology techniques – Artificial gene amplification and extension – Polymerase chain reaction – Anatomy – Digestive system – Gastrointestinal tract – Small intestine – Lymphatic system – Lymph nodes – Medicine and health sciences – Immune physiology – Immunology – Immune system – Research and analysis methods


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