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RefSeq (mRNA)



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CD99 antigen (Cluster of differentiation 99), also known as MIC2 or single-chain type-1 glycoprotein, is a heavily O-glycosylated transmembrane protein that is encoded by the CD99 gene in humans.[1][2][3] The protein has a mass of 32 kD. Unusually for a gene present on the X chromosome, the CD99 gene does not undergo X inactivation, and it was the first such pseudoautosomal gene to be discovered in humans.[4]


It is expressed on all leukocytes but highest on thymocytes[5][6][7] and is believed to augment T-cell adhesion [8][9] and apoptosis of double positive t cells.[10] It has been found in endothelial cells and in the periodontium, including gingival fibroblasts and gingival epithelial cells.[3] It also participates in migration and activation.[11] There is also experimental evidence that it binds to cyclophilin A.[12]

It is found on the cell surface of Ewing's sarcoma tumors [13] and is positive in granulosa cell tumors.[14] It is more expressed in malignant gliomas than in the brain, and such overexpression results in higher levels of invasiveness and lower rates of survival.[15] Antibodies to CD99 are used in diagnostic immunohistochemistry to distinguish Ewing's sarcoma from other tumours of similar histological appearance, as well as for the identification of thymic tumours, and of spindle cell tumours, such as synovial sarcoma, haemangiopericytoma, and meningioma.[4] EWS/FLI is thought to regulate CD99, but knockdown of EWS/FLI results in only a modest reduction in CD99. When CD99 expression is knocked down in human cells with Ewing's sarcoma and those cells are grafted onto mice, tumor and bone metastasis development is reduced.[13]

Reducing CD99 expression results in higher β-III tubulin expression and more neurite outgrowth.[13]

Upregulating CD99 expression in the cell line L428, a Hodgkin's lymphoma line, resulted in those cells redifferentiating towards B cells. Consequently, the loss of B-cell differentiation in Hodgkin's lymphoma may be due to CD99 downregulation.[16]

Men appear to express higher levels of CD99 than women.[17]

Prognostic Value

In patients with diffuse large B-cell lymphoma (DLBCL) with the germinal center B-cell (GCB, classified according to the Muris algorithm) subtype, positive expression of CD99 resulted in better 2-year event free survival (EFS) and 2-year overall survival (OS) compared to negative expression of CD99. In patients with DLBCL with non-GCB, however, negative expression of CD99 resulted in better 2-year EFS and 2-year OS.[18] In patients with non-small cell lung cancer (NSCLC), higher CD99 expression in the stroma results in better prognosis.[19]


There is evidence that through suppressing β1 integrin affinity, CD99 inhibits cell-extracellular matrix adhesion.[20]


  1. "Entrez Gene: CD99 CD99 molecule".
  2. Goodfellow P, Banting G, Sheer D, Ropers HH, Caine A, Ferguson-Smith MA, Povey S, Voss R (1983). "Genetic evidence that a Y-linked gene in man is homologous to a gene on the X chromosome". Nature. 302 (5906): 346–9. doi:10.1038/302346a0. PMID 6188056.
  3. 3.0 3.1 Krisanaprakornkit S, Chotjumlong P, Pata S, Chruewkamlow N, Reutrakul V, Kasinrerk W (January 2013). "CD99 ligation induces intercellular cell adhesion molecule-1 expression and secretion in human gingival fibroblasts". Arch. Oral Biol. 58 (1): 82–93. doi:10.1016/j.archoralbio.2012.06.011. PMID 22795566.
  4. 4.0 4.1 Leong AS-Y, Cooper K, Leong FJW-M (2003). Manual of Diagnostic Cytology (2nd ed.). Greenwich Medical Media, Ltd. pp. 145–146. ISBN 978-1-84110-100-2.
  5. Aussel C, Bernard G, Breittmayer JP, Pelassy C, Zoccola D, Bernard A (September 1993). "Monoclonal antibodies directed against the E2 protein (MIC2 gene product) induce exposure of phosphatidylserine at the thymocyte cell surface". Biochemistry. 32 (38): 10096–101. doi:10.1021/bi00089a027. PMID 8399135.
  6. Dworzak MN, Fritsch G, Buchinger P, Fleischer C, Printz D, Zellner A, Schöllhammer A, Steiner G, Ambros PF, Gadner H (January 1994). "Flow cytometric assessment of human MIC2 expression in bone marrow, thymus, and peripheral blood". Blood. 83 (2): 415–25. PMID 7506950.
  7. Choi EY, Park WS, Jung KC, Kim SH, Kim YY, Lee WJ, Park SH (July 1998). "Engagement of CD99 induces up-regulation of TCR and MHC class I and II molecules on the surface of human thymocytes". Journal of Immunology. 161 (2): 749–54. PMID 9670951.
  8. Bernard G, Raimondi V, Alberti I, Pourtein M, Widjenes J, Ticchioni M, Bernard A (October 2000). "CD99 (E2) up-regulates alpha4beta1-dependent T cell adhesion to inflamed vascular endothelium under flow conditions". European Journal of Immunology. 30 (10): 3061–5. doi:10.1002/1521-4141(200010)30:10<3061::AID-IMMU3061>3.0.CO;2-M. PMID 11069091.
  9. Kasinrerk W, Tokrasinwit N, Moonsom S, Stockinger H (January 2000). "CD99 monoclonal antibody induce homotypic adhesion of Jurkat cells through protein tyrosine kinase and protein kinase C-dependent pathway". Immunology Letters. 71 (1): 33–41. doi:10.1016/S0165-2478(99)00165-0. PMID 10709783.
  10. Bernard G, Breittmayer JP, de Matteis M, Trampont P, Hofman P, Senik A, Bernard A (March 1997). "Apoptosis of immature thymocytes mediated by E2/CD99". Journal of Immunology. 158 (6): 2543–50. PMID 9058785.
  11. Oh KI, Kim BK, Ban YL, Choi EY, Jung KC, Lee IS, Park SH (April 2007). "CD99 activates T cells via a costimulatory function that promotes raft association of TCR complex and tyrosine phosphorylation of TCR zeta". Experimental & Molecular Medicine. 39 (2): 176–84. doi:10.1038/emm.2007.20. PMID 17464179.
  12. Kim HJ, Chong KH, Kang SW, Lee JR, Kim JY, Hahn MJ, Kim TJ (September 2004). "Identification of cyclophilin A as a CD99-binding protein by yeast two-hybrid screening". Immunology Letters. 95 (2): 155–9. doi:10.1016/j.imlet.2004.07.001. PMID 15388255.
  13. 13.0 13.1 13.2 Rocchi A, Manara MC, Sciandra M, Zambelli D, Nardi F, Nicoletti G, Garofalo C, Meschini S, Astolfi A, Colombo MP, Lessnick SL, Picci P, Scotlandi K (March 2010). "CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis". J. Clin. Invest. 120 (3): 668–80. doi:10.1172/JCI36667. PMC 2827943. PMID 20197622.
  14. "CD99". NordiQC.
  15. Seol HJ, Chang JH, Yamamoto J, Romagnuolo R, Suh Y, Weeks A, Agnihotri S, Smith CA, Rutka JT (September 2012). "Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells". Genes Cancer. 3 (9–10): 535–49. doi:10.1177/1947601912473603. PMC 3591096. PMID 23486730.
  16. Zhou XH, Huang XP, Huang ZP, Wang ZQ, Zhao T (February 2013). "[CD99 regulates redifferentiation of classical Hodgkin's lymphoma cell line L428 towards B cells]". Nan Fang Yi Ke da Xue Xue Bao (in Chinese). 33 (2): 235–8. PMID 23443779.
  17. Lefèvre N, Corazza F, Duchateau J, Desir J, Casimir G (July 2012). "Sex differences in inflammatory cytokines and CD99 expression following in vitro lipopolysaccharide stimulation". Shock. 38 (1): 37–42. doi:10.1097/SHK.0b013e3182571e46. PMID 22575993.
  18. Hong J, Park S, Park J, Jang SJ, Ahn HK, Sym SJ, Cho EK, Shin DB, Lee JH (December 2012). "CD99 expression and newly diagnosed diffuse large B-cell lymphoma treated with rituximab-CHOP immunochemotherapy". Ann. Hematol. 91 (12): 1897–906. doi:10.1007/s00277-012-1533-z. PMID 22864685.
  19. Edlund K, Lindskog C, Saito A, Berglund A, Pontén F, Göransson-Kultima H, Isaksson A, Jirström K, Planck M, Johansson L, Lambe M, Holmberg L, Nyberg F, Ekman S, Bergqvist M, Landelius P, Lamberg K, Botling J, Ostman A, Micke P (November 2012). "CD99 is a novel prognostic stromal marker in non-small cell lung cancer". Int. J. Cancer. 131 (10): 2264–73. doi:10.1002/ijc.27518. PMID 22392539.
  20. Lee KJ, Lee SH, Yadav BK, Ju HM, Kim MS, Park JH, Jeoung D, Lee H, Hahn JH (March 2012). "The activation of CD99 inhibits cell-extracellular matrix adhesion by suppressing β(1) integrin affinity". BMB Rep. 45 (3): 159–64. doi:10.5483/BMBRep.2012.45.3.159. PMID 22449702.

Further reading

External links