プロジェクト1 – 横山チーム

小児がんや白血病を引き起こす分子メカニズムを探り新しい薬や診断法を生み出す

 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、発症には「MYC」というタンパク質が深く関わっています。このMYCが異常に産生されることががんの原因で、他の難治性小児がんにおいても重要な役割を果たしています。私たちは鶴岡でメタボローム解析を通じて「MYC」と「代謝」の関係性を明らかにし、がんの本質に迫りたいと考えています。そして「MYC関連がん」の新たな創薬や診断法の開発に取り組み、全ての小児がんに対する解決策を見出したいと思っています。

チームリーダー

横山 明彦Akihiko Yokoyama

1972年愛知県生まれ。
北海道大学理学部化学科卒業。同大学院理学研究科修士課程修了。
東京医科歯科大学医学研究科博士課程修了。
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。

提供可能な研究技術

■正常免疫マウスにおける白血病モデル
■初代培養骨髄前駆細胞を用いたex vivo培養系
■独自に開発した高感度クロマチン免疫沈降法

研究業績( *corresponding author)

2022
Tanaka A, Nakano T, Nomura M, Yamazaki H, Bewersdorf J, Mulet-Lazaro R, Hogg S, Liu B, Penson A, Yokoyama A, Zang W, Havermans M, Koizumi M, Hayashi Y, Cho H, Kanai A, Lee S, Xiao M, Koike Y, Zhang Y, Fukumoto M, Aoyama Y, Konuma T, Kunimoto H, Inaba T, Nakajima H, Honda H, Kawamoto H, Dell R, Abdel-Wahab O, Inoue D Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia. Blood  PMID: 35709354
DOI: 10.1182/blood.2021015325 https://pubmed.ncbi.nlm.nih.gov/35709354/

Koyaguchi T, Niida H, Motegi A, Sakai S, Uchida C, Ohata T, Iijima K, Yokoyama A, Suda T, Kitagawa M. Chromatin-remodeling factor BAZ1/ACF1 targets UV damage sites in an MLL1-dependent manner to facilitate nucleotide excision repair. BBA-Molecular Cell Research (2022)119332
DOI: https://doi.org/10.1016/j.bbamcr.2022.119332

Isobe T, Takagi M, Sato-Otsubo A, Nishimura A, Nagae G, Yamagishi C, Tamura M, Tanaka Y, Asada S, Takeda R, Tsuchiya A, Wang X, Yoshida K, Nannya Y, Ueno H, Akazawa R, Kato I, Mikami T, Watanabe K, Sekiguchi M, Seki M, Kimura S, Hiwatari M, Kato M, Fukuda S, Tatsuno K, Tsutsumi S, Kanai A, Inaba T, Shiozawa Y, Shiraishi Y, Chiba K, Tanaka H, Kotecha RS, Cruickshank MN, Ishikawa F, Morio T, Eguchi M, Deguchi T, Kiyokawa N, Arakawa Y, Koh K, Aoki Y, Ishihara T, Tomizawa D, Miyamura T, Ishii E, Mizutani S, Wilson NK, Göttgens B, Miyano S, Kitamura T, Goyama S, Yokoyama A, Aburatani H, Ogawa S, Takita J Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia Nature Communications (2022) 13:4501 DOI:https://doi.org/10.1038/s41467-022-32266-4

Shinriki S, Hirayama M, Nagamachi A, Yokoyama A, Kawamura T, Kanai A, Kawai H, Iwakiri J, Liu R, Maeshiro M, Tungalag S, Tasaki M, Ueda M, Tomizawa K, Kataoka N, Ideue T, Suzuki Y, Asai K, Tani T, Inaba T, and Matsui H DDX41 coordinates RNA splicing and transcriptional elongation to prevent DNA replication stress in hematopoietic cells Leukemia (2022) 36:2605-2620 DOI: https://doi.org/10.1038/s41375-022-01708-9

 

 

2021
*Yokoyama A. Role of the MOZ/MLL-mediated transcriptional activation system for self-renewal in normal hematopoiesis and leukemogenesis. The FEBS Journal (REVIEW, in press)

Yamamoto K, Goyama S, Asada S, Fujino T, Yonezawa T, Sato N, Takeda R, Tsuchiya A, Fukuyama T, Tanaka Y, Yokoyama A, Toya H, Kon A, Nannya Y, Onoguchi-Mizutani R, Nakagawa S, Hirose T, Ogawa S, Akimitsu N, Kitamura T A histone modifier, ASXL1, interacts with NONO and is involved in paraspeckle formation in hematopoietic cells. Cell Reports 36(8):109576. (2021) doi: 10.1016/j.celrep.2021.109576.

Takahashi S, Kanai A, Okuda H, Miyamoto R, Komata Y, Kawamura T, Matsui H, Inaba T, Takaori-Kondo A, *Yokoyama A. HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis. eLife 10:e65872 (2021) DOI: https://doi.org/10.7554/eLife.65872

Capodanno Y, Chen Y, Schrader J, Tomosugi M, Sumi S, Yokoyama A, Hiraoka N, Ohki R. Cross-talk among MEN1, p53 and Notch regulates the proliferation of pancreatic neuroendocrine tumor cells by modulating INSM1 expression and subcellular localization Neoplasia 23(9):979-992. (2021) doi: 10.1016/j.neo.2021.07.008

*Yokoyama A. Leukemogenesis via aberrant self-renewal by the MLL/AEP-mediated transcriptional activation system. Cancer Science (REVIEW) https://doi.org/10.1111/cas.15054

Miyamoto R, Kanai A, Okuda H, Komata Y, Takahashi S, Matsui H, Inaba T, *Yokoyama A. HOXA9 promotes MYC-mediated leukemogenesis by maintaining gene expression for multiple anti-apoptotic pathways. eLife 10:e64148 (2021) DOI: https://doi.org/10.7554/eLife.64148

Miyamoto R, and Yokoyama A. Protocol for fractionation-assisted native ChIP (fanChIP) to capture protein-protein/DNA interactions on chromatin. STAR Protocols 2, 100404 (2021) doi: https://doi.org/10.1016/j.xpro.2021.100404

 

2020
Takahashi S, Kanai A, Okuda H, Miyamoto R, Kawamura T, Matsui H, Inaba T, Takaori-Kondo A, *Yokoyama A. HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis. bioRxiv doi: https://doi.org/10.1101/2021.01.08.425834

Miyamoto R, Kanai A, Okuda H, Takahashi S, Matsui H, Inaba T, *Yokoyama A. HOXA9 promotes MYC-mediated leukemogenesis by maintaining gene expression for multiple anti-apoptotic pathways. bioRxiv doi: https://doi.org/10.1101/2020.10.20.347765

Nagamachi A, Kanai A, Nakamura M, Okuda H, Yokoyama A, Shinriki S, Matsui H, Inaba T Multi-organ failure with abnormal receptor metabolism in mice mimicking Samd9/9L syndromes J. Clin. Invest. (2020). https://doi.org/10.1172/JCI140147.

#Miyamoto R, #Okuda H, #Kanai A, Takahashi S, Kawamura T, Matsui H, Kitamura T, Kitabayashi I, Inaba T, *Yokoyama A Activation of CpG-rich promoters mediated by MLL drives MOZ-rearranged leukemia Cell Reports 32:13;108200 (2020) doi.org/10.1016/j.celrep.2020.108200 #co-first author

Takeda R, Asada S, Park SJ, Yokoyama A, Becker H, Kanai A, Visconte V, Hershberger C, Hayashi Y, Yonezawa T, Tamura M, Fukushima T, Tanaka Y, Fukuyama T, Matsumoto A, Yamasaki S, Nakai K, Yamazaki S, Inaba T, Shibata T, Inoue D, Honda H, Goyama S, Maciejewski J, Kitamura T. HHEX promotes myeloid transformation in cooperation with mutant ASXL1 Blood 136 (14): 1670–1684. (2020) DOI:10.1182/blood-2019-126663

Ochi Y, Kon A, Sakata T, Nakagawa MM, Nakazawa N, Kakuta M, Kataoka K, Koseki H, Nakayama M, Morishita D, Tsuruyama T, Saiki R, Yoda A, Okuda R, Yoshizato T, Yoshida K, Shiozawa Y, Nannya Y, Kotani S, Kogure Y, Kakiuchi N, Nishimura T, Makishima H, Malcovati L, Yokoyama A, Takeuchi K, Sugihara E, Sato T, Sanada M, Takaori-Kondo A, Cazzola M, Kengaku M, Miyano S, Shirahige K, Suzuki H, Ogawa S. Combined Cohesin-Runx1 deficiency synergistically perturbs chromatin looping and causes myelodysplastic syndromes. Cancer Discovery 10:836–53 (2020) DOI: 10.1158/2159-8290.CD-19-0982

Takahashi S, *Yokoyama A. The molecular functions of common and atypical MLL fusion protein complexes BBA – Gene Regulatory Mechanisms 1863(7):194548 (2020) [REVIEW] doi: 10.1016/j.bbagrm.2020.194548

Tatsumi G, Kawahara M, Imai T, Nishihata-Asai A, Nishida A, Inatomi O, Yokoyama A, Kakuta Y, Kito K, Andoh A. Thiopurine-mediated impairment of hamtopoietic stem and leukemia cells in Nudt15R138C knock-in mice. Leukemia 34(3):882-894 (2020) DOI ;10.1038/s41375-019-0583-9

Paubelle E, Zylbersztejn F, Maciel TT, Carvalho C, Mupo A, Cheok M, Lieben L, Sujobert P, Decroocq J, Yokoyama A, Asnafi V, Macintyre E, Tamburini J, Bardet V, Castaigne S, Preudhomme C, Dombret H, Carmeliet G, Bouscary D, Ginzburg YZ, de Thé H, Benhamou M, Monteiro RC, Vassiliou GS, Hermine O, Moura IC Vitamin D receptor controls cell stemness in acute myeloid leukemia and in normal bone marrow. Cell Reports. 30(3):739-754. (2020) doi: 10.1016/j.celrep.2019.12.055.

 

2019

*Yokoyama, A RNA polymerase II-dependent transcription initiated by selectivity factor 1: a central mechanism used by MLL fusion proteins in leukemic transformation (review) Frontiers in Genetics (RNA) 9:722 (2019)

 

2018
Asada S, Goyama S, Inoue D,  Shikata S,  Takeda R, Fukushima T,  Yonezawa T,  Fujino T, Hayashi Y, Kawabata K, Fukuyama T, Tanaka Y, Yokoyama, A Yamazaki S, Kozuka-Hata H, Oyama M, Kojima S,  Kawazu M, Mano H, Kitamura T Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis Nature Communications 9:2733 (2018)

Inoue D,  Fujino T,  Sheridan P,  Y Zhang Y,  Nagase R, Horikawa S, Li Z, Matsui H, Kanai A, Saika M,  Yamaguchi R,  Kozuka-Hata H,  Kawabata K,  Yokoyama, A,  Goyama S,  Inaba T,  Imoto S,  Miyano S,  Xu M,  Yang F,  Oyama M, and Kitamura T. A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies Leukemia 32:1327-1337 (2018)

 

2017
Okuda H, and *Yokoyama, A  In vivo leukemogenesis model using retrovirus transduction Bio-protcol 7:23, e2627 (2017)

Okuda H, and *Yokoyama, A  Myeloid progenitor transformation assay Bio-protcol 7:23, e2626 (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)