横山チーム

チームリーダー 横山明彦

1972年愛知県生まれ。東京医科歯科大学医学研究科卒業。取得学位は、医学博士。スタンフォード大学医学部リサーチアソシエイト、国立がん研究センターユニット長、京都大学医学研究科特定准教授を経て、2016年12月より国立がん研究センター・鶴岡連携研究拠点チームリーダー。白血病の分子メカニズムに関する研究に従事する。公益財団法人庄内地域産業振興センター・がんメタボロミクス研究顧問を兼務する。

研究概要 

(1)がんと代謝

がん細胞は増殖し続けるために必要な栄養を摂取するべく、代謝を変化させる。MYCという遺伝子にコードされるタンパク質は、がん細胞が細胞増殖に適した代謝システムを働かせる上で主要な役割を果たす。我々は、MYCが働く仕組みを明らかにし、MYCが制御するがん特異的な代謝物やその責任酵素を見出すことを目指す。またマウスを使ったがん発症モデルを使って、血中に現れる「がんの最も初期の段階を検出するバイオマーカー」を探索する。これらの研究の成果をもとにがんをできるだけ早期に検出する診断薬や、がん特異的な代謝を阻害する分子標的薬の創製を目指す。

(2)白血病の分子メカニズム

MLLという遺伝子の異常が、悪性度の高い急性白血病を引き起こす。私たちは様々なMLL変異体によって引き起こされる白血病のマウスモデルを構築し、発症のメカニズムを解明することを目指す。MLL遺伝子は染色体転座によって70以上の異なる融合パートナー遺伝子とキメラを形成する。しかし、MLLキメラは70通りの異なるメカニズムで白血病を引き起こすわけではなく、いくつかの基本原理に則った仕組みで、白血病発症を導いている。私たちはMLL関連白血病の基本原理を解明し、その理解に基づいた新たな治療法を発案する。

 
 

研究業績( *corresponding author)

2017

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)

#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)
PDF for press release

*Yokoyama, A. Transcriptional activation by MLL fusion proteins in leukemogenesis.(review) Experimental. Hematology 6:21–30 (2017)

2016

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)

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)

2015

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)
PDF for press release

*Yokoyama, A. Molecular mechanisms of MLL-associated leukemia.(review) Intl. J. Hematology 101:352-361 (2015).

2014

#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

2013

*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)

2011

*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)

2010

*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)

2008

*Yokoyama A and *Cleary ML. Menin critically links MLL proteins with LEDGF on cancer-associated target genes. Cancer Cell. 14:36-46 (2008) 

2005

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)

2004

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)

2003

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)

2002

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)

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)

2001

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)

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)

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)

Kawaguchi Y, Tanaka M, Yokoyama A, Matsuda G, Kato K, Kagawa H, Hirai K, and Roizman 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)

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)

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)

2000

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)

1998

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)

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)

1997

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)

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)

GALLERY