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Center for Stem Cell Biology and Regenerative Medicine

Division of Stem Cell and Molecular Medicine
幹細胞分子医学分野
Professor
Senior Assistant Professor
Assistant Professor
Assistant Professor
Project Assistant Professor
Project Assistant Professor
Project Assistant Professor

Atsushi Iwama, M.D., Ph.D.
Motohiko Oshima, Ph.D.
Yaeko Nakajima, Ph.D.
Masayuki Yamashita, M.D., Ph.D.
Takako Yokomizo, Ph.D.
Kazumasa Aoyama, Ph.D.
Shuhei Koide, Ph.D.

教 授
講 師助 教助 教
特任助教
特任助教
特任助教

博士（医学）
博士（医学）
博士（医学）
博士（医学）
博士（薬学）
博士（薬学）
博士（薬学）

岩大中山横青小間島島
下溝山出厚 志基 彦
やえ子
真 幸貴 子
和 正周 平Stem cells have the remarkable capacity to both self-renew and give rise to many
types of more specialized cells in the body, which explains their great therapeuticpotential in regenerative medicine. But that’s not the only reason stem cells havebecome such a hotbed of scientific inquiry. These cellular transformers also offer aninvaluable research tool for probing the disease mechanisms that underpin cancer,aging and a host of other health problems. Our major interest is to elucidate themechanisms of self-renewal and multi-lineage differentiation of hematopoietic stem
cells (HSCs). We are also interested in how the deregulated HSC functions areassociated with aging of our body and the development of age-related
hematological malignancies. We approach these issues mainly from the view pointof epigenetics.

1.  Polycomb repressive complex 1.1 coordinates
homeostatic and emergency myelopoiesis
Yaeko Nakajima-Takagi1, Motohiko Oshima1,Junichiro Takano2, Shuhei Koide1, Naoki Itokawa1,
Shun Uemura1, Masayuki Yamashita1, Shohei Andoh1, Kazumasa Aoyama1, Yusuke Isshiki4, Daisuke
Shinoda1, Atsunori Saraya4, Fumio Arai5, Kiyoshi
Yamaguchi6, Yoichi Furukawa6, Haruhiko Koseki2,Tomokatsu Ikawa3, and Atsushi Iwama1,7,81
Division of Stem Cell and Molecular Medicine,Center for Stem Cell Biology and RegenerativeMedicine, The Institute of Medical Science, The
University of Tokyo, Tokyo 108-8639, Japan. 2Laboratory for Developmental Genetics, RIKEN Centerfor Integrative Medical Sciences, Yokohama, Japan.
3
Division of Immunobiology, Research Institute for
Biomedical Sciences, Tokyo University of Science,Chiba 278-0022, Japan 4Department of Cellular andMolecular Medicine, Graduate School of Medicine,Chiba University, Chiba 260-8670, Japan 5Department of Stem Cell Biology and Medicine, Graduate
School of Medical Sciences, Kyushu University,Fukuoka 812-8582, Japan 6Division of Clinical Genome Research, Advanced Clinical Research Center,
The Institute of Medical Science, The University ofTokyo, Tokyo, Japan. 7Laboratoty of Cellular andMolecular Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo,Japan
Polycomb repressive complex (PRC) 1 regulates
stem cell fate by mediating mono-ubiquitination ofhistone H2A at lysine 119. While canonical PRC1 iscritical for hematopoietic stem and progenitor cell(HSPC) maintenance, the role of non-canonical PRC1
in hematopoiesis remains elusive. PRC1.1, a non-canonical PRC1, consists of PCGF1, RING1B, KDM2B,

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and BCOR. We recently showed that PRC1.1 insufficiency induced by the loss of PCGF1 or BCOR causes
myeloid-biased hematopoiesis and promotes transformation of hematopoietic cells in mice. Here weshow that PRC1.1 serves as an epigenetic switch thatcoordinates homeostatic and emergency hematopoiesis. PRC1.1 maintains balanced output of steady-state
hematopoiesis by restricting C/EBPαa-dependent
precocious myeloid differentiation of HSPCs and theHOXA9- and β-catenin-driven self-renewing network
in myeloid progenitors. Upon regeneration, PRC1.1 istransiently inhibited to facilitate formation of granulocyte-macrophage progenitor (GMP) clusters, thereby promoting emergency myelopoiesis. Moreover,constitutive inactivation of PRC1.1 results in unchecked expansion of GMPs and eventual transformation. Collectively, our results define PRC1.1 as anovel critical regulator of emergency myelopoiesis,
dysregulation of which leads to myeloid transformation.
2.  UTX inactivation in germinal center B cells
promotes the development of multiple myeloma with extramedullary disease
Ola Rizq1,2,3,4, Naoya Mimura3,5, Motohiko Oshima1,2, Shuji Momose6, Naoya Takayama7, Naoki Itokawa1, Shuhei Koide1, Asuka Shibamiya,3 Yurie Miyamoto-Nagai3,
MohamedRizk1,2,Yaeko
1,2
Nakajima-Takagi , Kazumasa Aoyama1,2, Changshan Wang2,8, Atsunori Saraya2, Ryoji Ito9, MasanoriSeimiya10, Mariko Watanabe11, Satoshi Yamasaki12,
Tatsuhiro Shibata12, Kiyoshi Yamaguchi13, Yoichi
Furukawa13, Tetsuhiro Chiba14, Emiko Sakaida3,5,Chiaki Nakaseko15, Jun-ichi Tamaru6, Yu-Tzu Tai4,Kenneth C. Anderson4, Hiroaki Honda16, and Atsushi Iwama1,2,171
Division of Stem Cell and Molecular Medicine,Center for Stem Cell Biology and RegenerativeMedicine, The Institute of Medical Science, The
University of Tokyo, Tokyo, Japan. 2Department ofCellular and Molecular Medicine, Graduate Schoolof Medicine, Chiba University, Chiba, Japan. 3Department of Hematology, Chiba University Hospital, Chiba, Japan 4Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology,Dana-Farber Cancer Institute, Harvard Medical
School, Boston, MA. 5Department of Transfusion
Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan. 6Department of Pathology,
Saitama Medical Center, Saitama Medical University, Kawagoe, Japan. 7Department of Regenerative
Medicine, Graduate School of Medicine, Chiba Uni-versity, Chiba, Japan. 8The State Key Laboratory ofReproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, China 9Central Institutefor Experimental Animals, Kanagawa, Japan 10Department of Medical Technology and Sciences,
School of Health Sciences at Narita, InternationalUniversity of Health and Welfare, Narita, Japan.
11Department of Clinical Laboratory, Chiba University Hospital, Chiba, Japan. 12Laboratory of Molecular Medicine, The Institute of Medical Science, The
University of Tokyo, Tokyo, Japan 13Division ofClinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The
University of Tokyo, Tokyo, Japan 14Department ofGastroenterology, Graduate School of Medicine,Chiba University, Chiba, Japan 15Department ofHematology, International University of Health andWelfare, Narita, Japan. 16Field of Human Disease
Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women’s Medical University, Tokyo, Japan. 17Laboratotyof Cellular and Molecular Chemistry, Graduate
School of Pharmaceutical Sciences, The Universityof Tokyo, Tokyo, Japan
UTX/KDM6A, a histone H3K27 demethylase anda key component of the COMPASS complex, is frequently lost or mutated in cancer; however, its tumor
suppressor function remains largely uncharacterized
in multiple myeloma (MM). Here, we show that theconditional deletion of the X-linked Utx in germinalcenter (GC) derived cells collaborates with the activating BrafV600E mutation and promotes induction oflethal GC/post-GC B cell malignancies with MM-likeplasma cell neoplasms being the most frequent. Micethat developed MM-like neoplasms showed expansion of clonal plasma cells in the bone marrow andextramedullary organs, serum M proteins, and anemia. Add-back of either wild-type UTX or a series ofmutants revealed that cIDR domain, that forms
phase-separated liquid condensates, is largely responsible for the catalytic activity-independent tumor suppressor function of UTX in MM cells. Utx loss in concert with BrafV600E only slightly induced MM-likeprofiles of transcriptome, chromatin accessibility, andH3K27 acetylation, however, it allowed plasma cells togradually undergo full transformation through activation of transcriptional networks specific to MM thatinduce high levels of Myc expression. Our results reveal a tumor suppressor function of UTX in MM and
implicate its insufficiency in the transcriptional reprogramming of plasma cells in the pathogenesis of MM.

Publications
1.		Melig G, Nobuhisa I, Saito K, Tsukahara R, Itabashi
A, Kanai Y, Kanai-Azuma M, Osawa M, Oshima

M, Iwama A, Taga T. A Sox17 downstream geneRasip1 is involved in the hematopoietic activity of

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intra-aortic hematopoietic clusters in the midgestation mouse embryo. Inflamm Regen 43(1):41,2023.
2.		Sawada D, Kato H, Kaneko H, Kinoshita D, Funayama S, Minamizuka T, Takasaki A, Igarashi K,Koshizaka M, Takada-Watanabe A, Nakamura R,
Aono K, Yamaguchi A, Teramoto N, Maeda Y,Ohno T, Hayashi A, Ide K, Ide S, Shoji M, Kitamoto T, Endo Y, Ogata H, Kubota Y, Mitsukawa N,Iwama A, Ouchi Y, Takayama N, Eto K, Fujii K,Takatani T, Shiohama T, Hamada H, Maezawa Y,
Yokote K. Senescence-associated inflammationand inhibition of adipogenesis in subcutaneous fatin Werner syndrome. Aging 15(19):9948-9964,2023.
3.		Nakajima-Takagi Y, Oshima M, Takano J, Koide S,
Itokawa N, Uemura S, Yamashita M, Andoh S,
Aoyama K, Isshiki Y, Shinoda D, Saraya A, Arai F,
Yamaguchi K, Furukawa Y, Koseki H, Ikawa T andIwama A. Polycomb repressive complex 1.1 coordinates homeostatic and emergency myelopoiesis.
eLife 12:e83004, 2023.
4.		Shibamiya A, Miyamoto-Nagai Y, Koide S, Oshima M, Rizq O, Aoyama K, Nakajima-Takagi Y,Kato R, Kayamori K, Isshiki Y, Oshima-Hasegawa
N, Muto T, Tsukamoto S, Takeda Y, Koyama-Nasu
R, Chiba T, Honda H, Yokote K, Iwama A, Sakaida
E, Mimura N. The pathogenetic significance of exhausted T cells in a mouse model of mature B cell
neoplasms. Cancer Immunol Immunother72(8):2635-2648, 2023.
5.		Rizq O, Mimura N, Oshima M, Momose S, Takayama N, Koide S, Shibamiya A, Nagai Y, Rizk M,Itokawa N, Nakajima-Takagi Y, Aoyama K, WangC, Saraya A, Seimiya M, Watanabe M, Yamasaki S,Shibata T, Yamaguchi K, Furukawa Y, Sakaida E,Nakaseko C, Tamaru J, Tai Y-T, Anderson KC,

Honda H, Iwama A. UTX inactivation in germinalcenter B cells promotes the development of multiple myeloma with extramedullary disease. Leukemia 37(9):1895-1907, 2023.
6.		Sorimachi Y, Kobayashi H, Shiozawa Y, Koide S,Nakato R, Shimizu Y, Okamura T, Shirahige K,Iwama A, Goda N, Takubo K, Takubo K. Mesenchymal loss of p53 alters stem cell capacity andmodels human soft tissue sarcoma traits. Stem
Cell Reports 18(5):1211-1226, 2023.
7.		Yokomizo-Nakano T, Hamashima A, Kubota S,Bai J, Sorin S, Sun Y, Kikuchi K, Iimori M, Morii M,
Kanai A, Iwama A, Huang G, Kurotaki D, Takizawa H, Matsui H, *Sashida G. Exposure to microbial products followed by loss of Tet2 promotes myelodysplastic syndrome via remodeling HSCs. JExp Med 220(7):e20220962, 2023.
8.		Mochizuki-Kashio M, Otsuki N, Fujiki K, Abdelhamd S, Kurre P, Grompe M, Iwama A, Saito K,Nakamura-Ishizu A. Replication stress increases
mitochondrial metabolism and mitophagy in
FANCD2 deficient fetal liver hematopoietic stem
cells. Front Oncol 13:1108430, 2023.
9.		Sakurai M, Ishitsuka K, Ito R, Wilkinson AC, Kimura T, Mizutani E, Nishikii H, Sudo K, Becker
HJ, Takemoto H, Sano T, Kataoka K, Takahashi S,
Nakamura Y, Kent, DG, Iwama A, Chiba S, Okamoto S, Nakauchi, H and Yamazaki S. Chemically-defined cytokine-free human hematopoietic
stem cell expansion. Nature 615(7950):127-133,2023.
10.	Jimbo K, Hattori A, Koide S, Ito T, Sasaki K, IwaiK, Nannya Y, Iwama A, Tojo A, and Konuma T.
Genetic deletion and pharmacologic inhibition ofE3 ubiquitin ligase HOIP impairs the propagationof myeloid leukemia. Leukemia 37:122-133, 2023.