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


Zdroje

1. Allen CE, Merad M, McClain KL. Langerhans-Cell Histiocytosis. N Engl J Med. 2018;379(9):856–68. Epub 2018/08/30. doi: 10.1056/NEJMra1607548 30157397.

2. Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116(11):1919–23. Epub 2010/06/04. blood-2010-04-279083 [pii] doi: 10.1182/blood-2010-04-279083 20519626.

3. Brown NA, Furtado LV, Betz BL, Kiel MJ, Weigelin HC, Lim MS, et al. High prevalence of somatic MAP2K1 mutations in BRAF V600E negative Langerhans cell histiocytosis. Blood. 2014. doi: 10.1182/blood-2014-05-577361 24982505.

4. Chakraborty R, Hampton OA, Shen X, Simko SJ, Shih A, Abhyankar H, et al. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood. 2014;124(19):3007–15. doi: 10.1182/blood-2014-05-577825 25202140.

5. Nelson DS, van Halteren A, Quispel WT, van den Bos C, Bovee JV, Patel B, et al. MAP2K1 and MAP3K1 mutations in langerhans cell histiocytosis. Genes Chromosomes Cancer. 2015;54(6):361–8. doi: 10.1002/gcc.22247 25899310.

6. Diamond EL, Subbiah V, Lockhart AC, Blay JY, Puzanov I, Chau I, et al. Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study. JAMA Oncol. 2018;4(3):384–8. Epub 2017/12/01. doi: 10.1001/jamaoncol.2017.5029 29188284; PubMed Central PMCID: PMC5844839.

7. Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte F, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013;121(9):1495–500. Epub 2012/12/22. doi: 10.1182/blood-2012-07-446286 23258922.

8. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med. 2015;373(8):726–36. doi: 10.1056/NEJMoa1502309 26287849; PubMed Central PMCID: PMC4971773.

9. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436(7051):720–4. Epub 2005/08/05. nature03890 [pii] doi: 10.1038/nature03890 16079850.

10. Vredeveld LC, Possik PA, Smit MA, Meissl K, Michaloglou C, Horlings HM, et al. Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis. Genes Dev. 2012;26(10):1055–69. Epub 2012/05/03. doi: 10.1101/gad.187252.112 22549727; PubMed Central PMCID: PMC3360561.

11. Tsao H, Goel V, Wu H, Yang G, Haluska FG. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol. 2004;122(2):337–41. Epub 2004/03/11. doi: 10.1046/j.0022-202X.2004.22243.x 15009714; PubMed Central PMCID: PMC2586668.

12. Allen CE, Li L, Peters TL, Leung HC, Yu A, Man TK, et al. Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol. 2010;184(8):4557–67. Epub 2010/03/12. jimmunol.0902336 [pii] doi: 10.4049/jimmunol.0902336 20220088.

13. Berres ML, Lim KP, Peters T, Price J, Takizawa H, Salmon H, et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med. 2014;211(4):669–83. doi: 10.1084/jem.20130977 24638167; PubMed Central PMCID: PMC3978272.

14. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE Jr., et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009;41(5):544–52. Epub 2009/03/14. ng.356 [pii] doi: 10.1038/ng.356 19282848; PubMed Central PMCID: PMC2705918.

15. Kaplan DH, Li MO, Jenison MC, Shlomchik WD, Flavell RA, Shlomchik MJ. Autocrine/paracrine TGFbeta1 is required for the development of epidermal Langerhans cells. J Exp Med. 2007;204(11):2545–52. Epub 2007/10/17. jem.20071401 [pii] doi: 10.1084/jem.20071401 17938236; PubMed Central PMCID: PMC2118472.

16. Lesche R, Groszer M, Gao J, Wang Y, Messing A, Sun H, et al. Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. Genesis. 2002;32(2):148–9. Epub 2002/02/22. doi: 10.1002/gene.10036 [pii]. 11857804.

17. Kuhn R, Schwenk F, Aguet M, Rajewsky K. Inducible gene targeting in mice. Science. 1995;269:1427–9. doi: 10.1126/science.7660125 7660125

18. Dankort D, Filenova E, Collado M, Serrano M, Jones K, McMahon M. A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev. 2007;21(4):379–84. Epub 2007/02/15. gad.1516407 [pii] doi: 10.1101/gad.1516407 17299132; PubMed Central PMCID: PMC1804325.

19. Hervier B, Haroche J, Arnaud L, Charlotte F, Donadieu J, Neel A, et al. Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation. Blood. 2014;124(7):1119–26. doi: 10.1182/blood-2013-12-543793 24894769.

20. Diamond EL, Durham BH, Haroche J, Yao Z, Ma J, Parikh SA, et al. Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms. Cancer Discov. 2016;6(2):154–65. doi: 10.1158/2159-8290.CD-15-0913 26566875; PubMed Central PMCID: PMC4744547.

21. Kaplan DH, Jenison MC, Saeland S, Shlomchik WD, Shlomchik MJ. Epidermal langerhans cell-deficient mice develop enhanced contact hypersensitivity. Immunity. 2005;23(6):611–20. Epub 2005/12/17. S1074-7613(05)00349-3 [pii] doi: 10.1016/j.immuni.2005.10.008 16356859.

22. Takahara K, Omatsu Y, Yashima Y, Maeda Y, Tanaka S, Iyoda T, et al. Identification and expression of mouse Langerin (CD207) in dendritic cells. Int Immunol. 2002;14(5):433–44. Epub 2002/04/30. doi: 10.1093/intimm/14.5.433 11978773.

23. Bursch LS, Wang L, Igyarto B, Kissenpfennig A, Malissen B, Kaplan DH, et al. Identification of a novel population of Langerin+ dendritic cells. J Exp Med. 2007;204(13):3147–56. Epub 2007/12/19. doi: 10.1084/jem.20071966 18086865; PubMed Central PMCID: PMC2150989.

24. Ginhoux F, Collin MP, Bogunovic M, Abel M, Leboeuf M, Helft J, et al. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J Exp Med. 2007;204(13):3133–46. Epub 2007/12/19. doi: 10.1084/jem.20071733 18086862; PubMed Central PMCID: PMC2150983.

25. Lenz A, Heine M, Schuler G, Romani N. Human and murine dermis contain dendritic cells. Isolation by means of a novel method and phenotypical and functional characterization. J Clin Invest. 1993;92(6):2587–96. Epub 1993/12/01. doi: 10.1172/JCI116873 8254016; PubMed Central PMCID: PMC288454.

26. Bigley V, McGovern N, Milne P, Dickinson R, Pagan S, Cookson S, et al. Langerin-expressing dendritic cells in human tissues are related to CD1c+ dendritic cells and distinct from Langerhans cells and CD141high XCR1+ dendritic cells. J Leukoc Biol. 2015;97(4):627–34. Epub 2014/12/18. doi: 10.1189/jlb.1HI0714-351R 25516751; PubMed Central PMCID: PMC4370053.

27. De Monte A, Olivieri CV, Vitale S, Bailleux S, Castillo L, Giordanengo V, et al. CD1c-Related DCs that Express CD207/Langerin, but Are Distinguishable from Langerhans Cells, Are Consistently Present in Human Tonsils. Front Immunol. 2016;7:197. Epub 2016/06/03. doi: 10.3389/fimmu.2016.00197 27252701; PubMed Central PMCID: PMC4879127.

28. Chang SY, Kweon MN. Langerin-expressing dendritic cells in gut-associated lymphoid tissues. Immunol Rev. 2010;234(1):233–46. Epub 2010/03/03. doi: 10.1111/j.0105-2896.2009.00878.x 20193022.

29. Chikwava K, Jaffe R. Langerin (CD207) staining in normal pediatric tissues, reactive lymph nodes, and childhood histiocytic disorders. Pediatr Dev Pathol. 2004;7(6):607–14. Epub 2005/01/05. doi: 10.1007/s10024-004-3027-z 15630529.

30. Kaser A, Ludwiczek O, Holzmann S, Moschen AR, Weiss G, Enrich B, et al. Increased expression of CCL20 in human inflammatory bowel disease. J Clin Immunol. 2004;24(1):74–85. Epub 2004/03/05. doi: 10.1023/B:JOCI.0000018066.46279.6b 14997037.

31. Welty NE, Staley C, Ghilardi N, Sadowsky MJ, Igyarto BZ, Kaplan DH. Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism. J Exp Med. 2013;210(10):2011–24. Epub 2013/09/11. doi: 10.1084/jem.20130728 24019552; PubMed Central PMCID: PMC3782055.

32. Chorro L, Sarde A, Li M, Woollard KJ, Chambon P, Malissen B, et al. Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network. J Exp Med. 2009;206(13):3089–100. Epub 2009/12/10. jem.20091586 [pii] doi: 10.1084/jem.20091586 19995948; PubMed Central PMCID: PMC2806478.

33. Tripp CH, Chang-Rodriguez S, Stoitzner P, Holzmann S, Stossel H, Douillard P, et al. Ontogeny of Langerin/CD207 expression in the epidermis of mice. J Invest Dermatol. 2004;122(3):670–2. Epub 2004/04/17. doi: 10.1111/j.0022-202X.2004.22337.x JID22337 [pii]. 15086552.

34. Schuster C, Vaculik C, Fiala C, Meindl S, Brandt O, Imhof M, et al. HLA-DR+ leukocytes acquire CD1 antigens in embryonic and fetal human skin and contain functional antigen-presenting cells. J Exp Med. 2009;206(1):169–81. Epub 2009/01/14. doi: 10.1084/jem.20081747 19139172; PubMed Central PMCID: PMC2626673.

35. Bergh A, Damber JE, van Rooijen N. Liposome-mediated macrophage depletion: an experimental approach to study the role of testicular macrophages in the rat. J Endocrinol. 1993;136(3):407–13. Epub 1993/03/01. doi: 10.1677/joe.0.1360407 8473830.

36. Cohen PE, Chisholm O, Arceci RJ, Stanley ER, Pollard JW. Absence of colony-stimulating factor-1 in osteopetrotic (csfmop/csfmop) mice results in male fertility defects. Biol Reprod. 1996;55(2):310–7. Epub 1996/08/01. doi: 10.1095/biolreprod55.2.310 8828834.

37. DeFalco T, Potter SJ, Williams AV, Waller B, Kan MJ, Capel B. Macrophages Contribute to the Spermatogonial Niche in the Adult Testis. Cell Rep. 2015;12(7):1107–19. Epub 2015/08/11. doi: 10.1016/j.celrep.2015.07.015 26257171; PubMed Central PMCID: PMC4545310.

38. Mossadegh-Keller N, Gentek R, Gimenez G, Bigot S, Mailfert S, Sieweke MH. Developmental origin and maintenance of distinct testicular macrophage populations. J Exp Med. 2017;214(10):2829–41. Epub 2017/08/09. doi: 10.1084/jem.20170829 28784628; PubMed Central PMCID: PMC5626405.

39. Ansar Ahmed S, Dauphinee MJ, Talal N. Effects of short-term administration of sex hormones on normal and autoimmune mice. J Immunol. 1985;134(1):204–10. Epub 1985/01/01. 3964814.

40. Weinstein Y, Berkovich Z. Testosterone effect on bone marrow, thymus, and suppressor T cells in the (NZB X NZW)F1 mice: its relevance to autoimmunity. J Immunol. 1981;126(3):998–1002. Epub 1981/03/01. 6450808.

41. Wu J, Henning P, Sjogren K, Koskela A, Tuukkanen J, Moverare-Skrtic S, et al. The androgen receptor is required for maintenance of bone mass in adult male mice. Mol Cell Endocrinol. 2019;479:159–69. Epub 2018/10/12. doi: 10.1016/j.mce.2018.10.008 30308267.

42. Antoniou-Tsigkos A, Zapanti E, Ghizzoni L, Masorakos G. Adrenal Androgens. South Dartmouth, MA: MDText.com, Inc.; 2019.

43. Haroche J, Charlotte F, Arnaud L, von Deimling A, Helias-Rodzewicz Z, Hervier B, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood. 2012;120(13):2700–3. Epub 2012/08/11. doi: 10.1182/blood-2012-05-430140 22879539.

44. Emile JF, Diamond EL, Helias-Rodzewicz Z, Cohen-Aubart F, Charlotte F, Hyman DM, et al. Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease. Blood. 2014;124(19):3016–9. doi: 10.1182/blood-2014-04-570937 25150293; PubMed Central PMCID: PMC4224196.

45. Douillard P, Stoitzner P, Tripp CH, Clair-Moninot V, Ait-Yahia S, McLellan AD, et al. Mouse lymphoid tissue contains distinct subsets of langerin/CD207 dendritic cells, only one of which represents epidermal-derived Langerhans cells. J Invest Dermatol. 2005;125(5):983–94. Epub 2005/11/22. doi: 10.1111/j.0022-202X.2005.23951.x 16297200.

46. Arceci RJ, Allen CE, Dunkel I, Jacobsen ED, Whitlock J, Vassallo R, et al. Evaluation of afuresertib, an oral pan-AKT inhibitor, in patients with Langehans cell histiocytosis. Blood. 2013;122(21):2907.

47. Arceci RJ, Allen CE, Dunkel IJ, Jacobsen E, Whitlock J, Vassallo R, et al. A phase IIa study of afuresertib, an oral pan-AKT inhibitor, in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2017;64(5). Epub 2016/11/03. doi: 10.1002/pbc.26325 27804235.

48. Heritier S, Saffroy R, Radosevic-Robin N, Pothin Y, Pacquement H, Peuchmaur M, et al. Common cancer-associated PIK3CA activating mutations rarely occur in Langerhans cell histiocytosis. Blood. 2015;125(15):2448–9. doi: 10.1182/blood-2015-01-625491 25858893.

49. Weintraub M, Bhatia KG, Chandra RS, Magrath IT, Ladisch S. p53 expression in Langerhans cell histiocytosis. J Pediatr Hematol Oncol. 1998;20(1):12–7. 9482407.


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