Diagnosis and treatment of Langerhans cell histiocytosis by KIR2DL4

• Project/Area Number: 16K19080
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Kyoto University
• Principal Investigator: ueshima chiyuki 京都大学, 医学研究科, 技術職員 (80759449)
• Research Collaborator: Takei Yusuke ; Hirata Masahiro ; Sugimoto Akihiko ; Kurata Mariyo ; Moriyoshi Koki ; Haga Hironori
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: KIR2DL4 / ヒトランゲルハンス細胞組織球症 / ERK / SHP-2 / ランゲルハンス細胞組織球症(LCH) / inhibitory receptor / ランゲルハンス細胞組織球症

Outline of Final Research Achievements

We examined the expression and function of KIR2DL4 in LCHs. In pathological specimens, 27 of 36 LCH cases (75.0%) were immunohistochemically positive for KIR2DL4. Its expression was independent of age, gender, location, multi-or single-system, and the status of BRAFV600E immunostaining. We also confirmed the expression of KIR2DL4 mRNA and protein in the human LCH-like cell lines ELD- 1 and PRU-1. KIR2DL4 protein was distributed in the membrane and cytoplasm of ELD-1 cells, but only in the cytoplasm of PRU-1 cells. An agonistic antibody against KIR2DL4 reduced phosphorylation of extracellular signal-regulated kinases (ERKs) and suppressed the cell growth of ELD-1 cells in a Src homology region 2 domain-containing phosphatase-2 dependent manner, but it had no effect in PRU-1 cells. These results suggest that KIR2DL4-mediated ERK suppression is a possible therapeutic target for LCH cells.

Research Products

• [Journal Article] Killer cell immunoglobulin-like receptor 2DL4 is expressed in and suppresses the cell growth of Langerhans cell histiocytosis. (2017)
  • Author(s): Takei Y, Ueshima C, Kataoka TR, Hirata M, Sugimoto A, Rokutan-Kurata M, Moriyoshi K, Ono K, Murakami I, Iwamoto S, Haga H.
  • Journal Title: Oncotarget Volume: 8 Issue: 23 Pages: 36964-36972
  • DOI: 10.18632/oncotarget.16936
  • Peer Reviewed / Open Access
• [Journal Article] CEACAM1 long isoform has opposite effects on the growth of human mastocytosis and medullary thyroid carcinoma cells. (2017)
  • Author(s): Chiyuki Ueshima, Tatsuki R. Kataoka, Yusuke Takei, Masahiro Hirata, Akihiko Sugimoto, Mitsuyoshi Hirokawa, Yoshimichi Okayama, Richard S. Blumberg, Hironori Haga.
  • Journal Title: Cancer med. Volume: - Issue: 4 Pages: 845-856
  • DOI: 10.1002/cam4.1050
  • NAID: 120006309310
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Possible inducible skin-associated lymphoid tissues (iSALT)-like structures with CXCL13+ fibroblast-like cells in secondary syphilis (2017)
  • Author(s): Kogame T, Nomura T, Kataoka T, Hirata M, Ueshima C, Matsui M, Kabashima K
  • Journal Title: Br J Dermatol Volume: in press Issue: 6 Pages: 1737-1739
  • DOI: 10.1111/bjd.15349
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Case of Noonan Syndrome with Multiple Subcutaneous Tumours with MAPK-ERK/p38 Activation. (2016)
  • Author(s): Honda T, Kataoka TR, Ueshima C, Miyachi Y, Kabashima K.
  • Journal Title: Acta Derm Venereol. Volume: 96 Pages: 130-131
  • NAID: 120006305918
• [Journal Article] Clinical, Morphologic, and Pathologic Features Associated With Increased FDG Uptake in Schwannoma. (2016)
  • Author(s): Miyake KK, Nakamoto Y, Kataoka TR, Ueshima C, Higashi T, Terashima T, Nakatani K, Saga T, Minami S, Togashi K.
  • Journal Title: AJR Am J Roentgenol. Volume: 207 Pages: 1288-1296
• [Presentation] ヒトマスト細胞はKIR2DL4を発現し、妊娠成立に関与する (2016)
  • Author(s): 上島 千幸、片岡 竜貴、平田 勝啓、南口 早智子、羽賀 博典、
  • Organizer: 第13回日本病理学会カンファレンス
  • Place of Presentation: 六甲山ホテル