チームリーダー

横山明彦

Akihiko Yokoyama

0816-0081.JPG

いつか全ての小児がんに対する解決策を

私は、長年MLLという遺伝子に異常を持つ白血病の研究に携わってきました。この白血病は乳児に多く、治りにくいという特徴があり、新たな治療法の開発が切望されています。MLL関連白血病の発症においてMYCというタンパク質が深く関わっています。MYCはよく知られたがん遺伝子であり、遺伝子異常によってMYCファミリータンパク質が異常に産生されることが、様々ながんの原因となっています。神経芽細胞腫など他の難治性小児がんにおいても、MYCが重要な役割を果たしています。私たちはここ鶴岡で「MYC」と「代謝」の関係性を明らかにすることでがんの本質に迫れると考えています。メタボローム(代謝物)解析を通じて、様々な「MYC関連がん」の新たな創薬や診断法の開発に取り組みます。そしてその先にいつか、全ての小児がんに対する解決策を見出したいという夢を持っています。

 

研究業績

発表論文( *corresponding author)

  1. Chen Y,  Anastassiadis K, Kranz A, Stewart AF, Arndt K, Waskow C, Yokoyama A, Jones K, Neff T, Lee Y, Ernst P. MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia. Cancer Cell 31:6, p755-770 (2017)
  2. #Okuda H, #Stanojevic B, Kanai A, Kawamura T, Takahashi S, Matsui H, Takaori-Kondo A, *Yokoyama A. Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia. J. Clin. Invest. 127(5) 1918-1931#co-first author (2017)
  3. *Yokoyama, A. Transcriptional activation by MLL fusion proteins in leukemogenesis.(review) Experimental. Hematology 6:21–30 (2017)
  4. Okuda H, Takahashi S, Takaori-Kondo A, *Yokoyama A. TBP loading by AF4 through SL1 is the major rate-limiting step in MLL fusion-dependent transcription. Cell Cycle 15:20, 2712-2722, (2016)
  5. Kadono M, Kanai A, Nagamachi A, Shinriki S, Kanata J, Iwato K, Kyo T, Ochima K, Yokoyama A, Kawamura T, Nagase R, Inoue D, Kitamura T, Inaba T, Ichinohe T, Matsui H. Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia Experimental Hematology 44:745-754 (2016)
  6. Okuda H,  Kanai A,  Ito S,  Matsui H,  *Yokoyama A. AF4 utilizes the SL1 components of RNAP1 machinery to initiate MLL fusion- and AEP-dependent transcription Nature Communications 6:8869 (2015)
  7. *Yokoyama, A. Molecular mechanisms of MLL-associated leukemia.(review) Intl. J. Hematology 101:352-361 (2015).
  8. #Okuda H, #Kawaguchi M, #Kanai A, #Matsui H, Kawamura T, Inaba T, Kitabayashi I,  *Yokoyama A. MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters Nucleic Acids Research  42:7 4241-4256 (2014) #co-first author
  9. *Yokoyama A, Ficara F, Murphy M, Meisel C, Hatanaka C, Kitabayashi I, *Cleary ML. MLL becomes functional through intra-molecular interaction not by proteolytic processing. PLOS ONE 8(9):e73649 (2013)
  10. *Yokoyama A, Ficara F, Murphy M, Meisel C, Naresh A, Kitabayashi I, *Cleary ML. Proteolytically cleaved MLL subunits are susceptible to distinct degradation pathways. J. Cell Sci. 124(13): 2208-19 (2011)
  11. *Yokoyama A, Lin M, Naresh A, Kitabayashi I, *Cleary ML .A higher-order complex containing AF4- and ENL-family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell.17(2): 198-212 (2010)
  12. *Yokoyama A and *Cleary ML. Menin critically links MLL proteins with LEDGF on cancer-associated target genes. Cancer Cell. 14:36-46 (2008) 
  13. Yokoyama A, Somervaille TCP, Smith KS, Rosenblatt-Rosen O, Meyerson M, Cleary ML .The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell. 21(123):207-218 (2005)
  14. Yokoyama A, Wang Z, Wysocka J, Sanyal M, Aufiero D, Kitabayashi I, Herr W, Cleary ML. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression Mol. Cell. Biol. 24(13):5639-5649 (2004)
  15. Kato K, Yokoyama A, Tohya Y, Akashi H, Nishiyama Y, Kawaguchi Y. Identification of protein kinases responsible for phosphorylation of Epstein–Barr virus nuclear antigen leader protein at serine-35, which regulates its coactivator function J. Gen. Virol. 84;3381-3392 (2003)
  16. Yokoyama A, Kitabayashi I, Ayton PM, Cleary ML, Ohki M. Leukemia proto-oncoprotein MLL is proteolytically processed into two fragments with opposite transcriptional properties. Blood. Nov 15;100(10):3710-8. (2002)
  17. Tanaka M, Yokoyama A, Igarashi M, Matsuda G, Kato K, Kanamori M, Hirai K, Kawaguchi Y, Yamanashi Y. Conserved region CR2 of Epstein-Barr virus nuclear antigen leader protein is a multifunctional domain that mediates self-association as well as nuclear localization and nuclear matrix association. J. Virol. 76(3):1025-32. (2002)
  18. Kitabayashi I, Aikawa Y, Nguyen LA, Yokoyama A, Ohki M. Activation of AML1-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein. EMBO J. 20(24):7184-96. (2001)
  19.  Yokoyama A, Tanaka M, Matsuda G, Kato K, Kanamori M, Kawasaki H, Hirano H, Kitabayashi I, Ohki M, Hirai K, *Kawaguchi Y.  Identification of Major Phosphorylation Sites of Epstein-Barr Virus Nuclear Antigen Leader Protein (EBNA-LP): The function of EBNA-LP to Induce Latent Membrane Protein 1 Cooperatively with EBNA-2 Is Regulated by Phosphorylation. J.Virol. 75(11):5119-5128 (2001)
  20. Kato K, Kawaguchi Y, Tanaka M, Igarashi M, Yokoyama A, Matsuda G, Kanamori M, Nakajima K, Nishimura Y, Shimojima M, Hang TT, Takahashi E, Hirai K Epstein-Barr Virus Encoded-Protein Kinase BGLF4 Mediates Hyper-phosphorylation of Cellular Elongation Factor 1d (EF-1d): EF-1d is Universally Modified by Conserved Protein Kinases of Herpesviruses in Mammalian Cells. J.Gen.Virol. 82(6):1457-63 (2001)
  21. Kawaguchi Y, Tanaka M, Yokoyama A, Matsuda G, Kato K, Kagawa H, Hirai K, andRoizman B. Herpes simplex virus a regulatory protein ICP0 functionally interacts with a cellular transcription factor BMAL1. Proc. Natl. Acad. Sci. USA  98(4) 1877-1882 (2001)
  22. Yokoyama A, Kawaguchi K, Kitabayashi I, Ohki M, Hirai K. The Conserved Domain CR2 of Epstein-Barr Virus Nuclear Antigen Leader Protein is Responsible Not Only for Nuclear Matrix Association But Also for Nuclear Localization. Virology  279, 401-413 (2001)
  23. Kitabayashi I, Aikawa Y, Yokoyama A, Hosoda F, Nagai M, Kakazu N, Abe T, Ohki M. Fusion of MOZ and p300 hitone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation. Leukemia 15 89-94 (2001)
  24. Kawaguchi Y, Nakajima K, Igarashi M, Morita T, Tanaka M, Suzuki M, Yokoyama A, Matsuda G, Kato K, Kanamori M, Hirai K. Interaction of epstein-barr virus nuclear antigen leader protein (EBNA-LP) with HS1-associated protein X-1: implication of cytoplasmic function of EBNA-LP. J. Virol. 74(21):10104-11. (2000)
  25. Kitabayashi I, Yokoyama A, Shimizu K, Ohki M. Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation. EMBO J. Jun 1;17(11):2994-3004. (1998)
  26. Kitabayashi I, Ida K, Morohoshi F, Yokoyama A, Mitsuhashi N, Shimizu K, Nomura N, Hayashi Y, Ohki M. The AML1-MTG8 leukemic fusion protein forms a complex with a novel member of the MTG8(ETO/CDR) family, MTGR1. Mol. Cell. Biol. 18(2):846-58. (1998)
  27. Yokoyama A, Karasaki H, Urushibara N, Nomoto K, Imai Y, Nakamura K, Mizuno Y, Ogawa K, Kikuchi K. The characteristic gene expressions of MAPK phosphatases 1 and 2 in hepatocarcinogenesis, rat ascites hepatoma cells, and regenerating rat liver. Biochem. Biophys. Res. Commun. 29;239(3):746-51. (1997)
  28. Kaya S, Yokoyama A, Imagawa T, Taniguchi K, Froehlich JP, Albers RW. Cloning of the eel electroplax Na+,K(+)-ATPase alpha subunit.  Ann. N Y Acad. Sci. 834:129-31. (1997)