リンパ腫幹細胞に着目した難治性リンパ腫の分子病理学的メカニズムの探索研究

• Project/Area Number: 15K19053
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Okayama University
• Principal Investigator: 高田 尚良 岡山大学, 医歯(薬)学総合研究科, 講師 (90580259)
• Project Period (FY): 2015-04-01 – 2016-03-31
• Project Status: Discontinued (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 人体病理 / 血液 / 悪性リンパ腫 / リンパ腫幹細胞

Outline of Annual Research Achievements

これまで検討してきた濾胞性リンパ腫におけるTRA-1-60陽性細胞集団が薬剤抵抗性を示し、強い腫瘍形成能を有することを見出した。（現在論文投稿中）本年度では、濾胞性リンパ腫細胞株からこのTRA-1-60陽性細胞集団をセルソーターを用いて純化し、網羅的発現解析を行った。特に薬剤抵抗性を示す遺伝子について、複数の細胞株を用いて遺伝子の絞込みを行ったところ、複数の薬剤代謝あるいは薬剤排泄にかかわる遺伝子発現がこのTRA-1-60陽性集団で上昇していることが判明した。real-time PCRによる検討でも同様の結果となった。さらに、タンパク発現レベルについて、複数の患者病理組織（FFPET)を用いて二重染色法により検討したところ、TRA-1-60陽性細胞に一致して共発現がみられた。これらの結果より、薬剤代謝、排泄にかかわる遺伝子群がTRA-1-60陽性細胞（リンパ腫幹細胞集団）で重要な役割を果たしていると考えられる。また、他の難治性リンパ腫であるマントル細胞リンパ腫についても同様に患者組織検体においてTRA-1-60の染色を行い、少数のTRA-1-60陽性集団が血管周囲に存在しすることを見出した。さらに、マントル細胞リンパ腫由来のリンパ腫においても少数であるがTRA-1-60集団が存在し、それらが薬剤耐性を示すことが判明した。（現在論文準備中）TRA-1-60陽性細胞に代表されるリンパ腫幹細胞が亜型を問わず治療抵抗性に関わる可能性があり、他の亜型についての検討やそのメカニズムについての検索が必要である。

Research Products

• [Journal Article] The role of "watch and wait" in intestinal follicular lymphoma in rituximab era. (2016)
  • Author(s): Tari A, Asaoku H, Takata K, Fujimori S, Tanaka S, Fujihara M, Koga T, Yoshino T.
  • Journal Title: Scand J Gastroenterol Volume: 51 Issue: 3 Pages: 321-8
  • DOI: 10.3109/00365521.2015.1087589
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lymphoid hyperplasia of the colon and its association with underlying allergic airway diseases. (2016)
  • Author(s): Iwamuro M, Hiraoka S, Okada H, Kawai Y, Miyabe Y, Takata K, Kawano S, Yamamoto K.
  • Journal Title: Int J Colorectal Dis. Volume: 31 Issue: 2 Pages: 313-7
  • DOI: 10.1007/s00384-015-2392-6
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Colorectal Manifestation of Follicular Lymphoma (2016)
  • Author(s): Iwamuro M, Okada H, Takata K, Takenaka R, Inaba T, Mizuno M, Kobashi H, Tanaka S, Yoshioka M, Kondo E, Yoshino T, Yamamoto K.
  • Journal Title: Internal Medicine Volume: 55 Issue: 1 Pages: 1-8
  • DOI: 10.2169/internalmedicine.55.5393
  • NAID: 130005116794
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Frequent MYD88 L265P and CD79B Mutations in Primary Breast Diffuse Large B-Cell Lymphoma. (2016)
  • Author(s): Taniguchi K, Takata K, Chuang SS, Miyata-Takata T, Sato Y, Satou A, Hashimoto Y, Tamura M, Nagakita K, Ohnishi N, Noujima-Harada M, Tabata T, Kikuti YY, Maeda Y, Nakamura N, Tanimoto M, Yoshino T.
  • Journal Title: Am J Surg Pathol. Volume: 40 Issue: 3 Pages: 324-34
  • DOI: 10.1097/pas.0000000000000592
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Diagnosis of follicular lymphoma of the gastrointestinal tract: A better initial diagnostic workup. (2016)
  • Author(s): Iwamuro M, Kondo E, Takata K, Yoshino T, Okada H.
  • Journal Title: World J Gastroenterology Volume: 22 Issue: 4 Pages: 1674-83
  • DOI: 10.3748/wjg.v22.i4.1674
  • Peer Reviewed / Open Access
• [Journal Article] Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization. (2016)
  • Author(s): Hayashi K, Michiue H, Yamada H, Takata K, Nakayama H, Wei FY, Fujimura A, Tazawa H, Asai A, Ogo N, Miyachi H, Nishiki T, Tomizawa K, Takei K, Matsui H.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 23372-23372
  • DOI: 10.1038/srep23372
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin 13-positive mast cells are increased in immunoglobulin G4-related sialadenitis. (2015)
  • Author(s): Takeuchi M, Ohno K, Takata K, Gion Y, Tachibana T, Orita Y, Yoshino T, Sato Y.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 7696-7696
  • DOI: 10.1038/srep07696
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] T-cell receptor (TCR) phenotype of nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL): a clinicopathologic study of 39 cases. (2015)
  • Author(s): Kato S, Asano N, Miyata-Takata T, Takata K, Elsayed AA, Satou A, Takahashi E, Kinoshita T, Nakamura S.
  • Journal Title: Am J Surg Pathol. Volume: 39 Issue: 4 Pages: 462-71
  • DOI: 10.1097/pas.0000000000000323
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Magnified endoscopic features of duodenal follicular lymphoma and other whitish lesions. (2015)
  • Author(s): Iwamuro M, Okada H, Takata K, Kawai Y, Kawano S, Nasu J, Kawahara Y, Tanaka T, Yoshino T, Yamamoto K.
  • Journal Title: Acta Medica Okayama Volume: 69 Pages: 37-44
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Primary Cutaneous Extranodal Natural Killer/T-Cell Lymphoma Misdiagnosed as Peripheral T-Cell Lymphoma: The Importance of Consultation/Referral and Inclusion of EBV In Situ Hybridization for Diagnosis. (2015)
  • Author(s): Win KT, Liau JY, Chen BJ, Takata K, Chen CY, Li CC, Hsiao CH, Chuang SS.
  • Journal Title: Appl Immunohistochem Mol Morphol. Volume: 24 Issue: 2 Pages: 105-11
  • DOI: 10.1097/pai.0000000000000162
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cytokeratin-positive Fibroblastic Reticular Cell Tumor With Follicular Dendritic Cell Features: A Case Report and Review of the Literature. (2015)
  • Author(s): Goto N, Tsurumi H, Takami T, Futamura M, Morimitsu K, Takata K, Sato Y, Yoshino T, Adachi S, Saito K, Yamakawa M.
  • Journal Title: Am J Surg Pathol. Volume: 39 Issue: 4 Pages: 573-580
  • DOI: 10.1097/pas.0000000000000362
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis (2015)
  • Author(s): Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Nagata K, Horie Y, Hayashi K, Imamura T, Morimoto A, Imashuku S, Gogusev J, Jaubert F, Takata K, Oka T, Yoshino T.
  • Journal Title: Cell Commun Signal Volume: 13 Issue: 1 Pages: 13-13
  • DOI: 10.1186/s12964-015-0092-z
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathologic analysis of 6 lymphomatoid gastropathy cases: expanding the disease spectrum to CD4-CD8+ cases. (2015)
  • Author(s): Takata K, Noujima-Harada M, Miyata-Takata T, Ichimura K, Sato Y, Miyata T, Naruse K, Iwamoto T, Tari A, Masunari T, Sonobe H, Okada H, Iwamuro M, Mizobuchi K, Gion Y, Yoshino T.
  • Journal Title: Am J Surg Pathol. Volume: 39 Issue: 9 Pages: 1259-66
  • DOI: 10.1097/pas.0000000000000443
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Serum level of soluble interleukin-2 receptor correlates with CD25 expression in patients with T lymphoblastic lymphoma. (2015)
  • Author(s): Toji T, Takata K, Sato Y, Miyata-Takata T, Hayashi E, Habara T, Maeda Y, Tanimoto M, Yoshino T.
  • Journal Title: J Clin Pathol. Volume: 68 Issue: 8 Pages: 622-7
  • DOI: 10.1136/jclinpath-2015-202934
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A multicenter survey of enteroscopy for the diagnosis of intestinal follicular lymphoma. (2015)
  • Author(s): Iwamuro M, Okada H, Kawano S, Shiode J, Takenaka R, Imagawa A, Inaba T, Suzuki S, Nishimura M, Mizuno M, Araki M, Mannami T, Ueki T, Kobashi H, Fukatsu H, Tanaka S, Omoto A, Kawai Y, Kitagawa T, Toyokawa T, Takata K, Yoshino T, Takaki A, Yamamoto K.
  • Journal Title: Oncol Letter Volume: 10 Pages: 131-136
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Magnifying Endoscopic Observation of Duodenal Involvement of Follicular Lymphoma before and after Chemotherapy (2015)
  • Author(s): Iwamuro M, Okada H, Takata K, Fujii N, Kawano S, Kawahara Y, Yoshino T, Yamamoto K.
  • Journal Title: Internal Medicine Volume: 54 Issue: 14 Pages: 1741-1745
  • DOI: 10.2169/internalmedicine.54.4390
  • NAID: 130005088253
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan. (2015)
  • Author(s): Tomita S, Kikuti YY, Carreras J, Kojima M, Ando K, Takasaki H, Sakai R, Takata K, Yoshino T, Bea S, Campo E, Nakamura N.
  • Journal Title: Modern Pathology Volume: 28 Issue: 10 Pages: 1286-96
  • DOI: 10.1038/modpathol.2015.85
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A subset of ocular adnexal marginal zone lymphomas may arise in association with IgG4-related disease. (2015)
  • Author(s): Ohno K, Sato Y, Ohshima K, Takata K, Miyata-Takata T, Takeuchi M, Gion Y, Tachibana T, Orita Y, Ito T, Swerdlow SH, Yoshino T.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 13539-13539
  • DOI: 10.1038/srep13539
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Spontaneous regression of plasmablastic lymphoma in an elderly human immunodeficiency virus (HIV)-negative patient. (2015)
  • Author(s): Igawa T, Sato Y, Kawai H, Kondo E, Takeuchi M, Miyata-Takata T, Takata K, Yoshino T.
  • Journal Title: Diagnostic Pathology Volume: 10 Issue: 1 Pages: 183-183
  • DOI: 10.1186/s13000-015-0421-y
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Elevation of serum interleukins 8, 4, and 1β levels in patients with gastrointestinal low-grade B-cell lymphoma. (2015)
  • Author(s): Miyata-Takata T, Takata K, Toji T, Goto N, Kasahara S, Takahashi T, Tari A, Noujima-Harada M, Miyata T, Sato Y, Yoshino T.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 18434-18434
  • DOI: 10.1038/srep18434
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Rare T/NK-cell neoplasma: cutaneous NK/T cell lymphoma and indolent T-cell lymphoma (2015)
  • Author(s): Katsuyoshi Takata, Tadashi Yoshino
  • Organizer: 日本リンパ網内系学会
  • Place of Presentation: 岡山
  • Year and Date: 2015-07-09
  • Invited