The 21st IRCMS Symposium on

The Dynamics and Development of
Normal and Malignant
Hematopoietic Stem Cells
Date & Time : 13:00-17:40 (JST), 20th February 2024
9:00-12:20 (JST), 21st February 2024
Venue : Onsite and Online (IRCMS Lounge, Kumamoto University and Zoom)
Organized by Goro Sashida
Supported by Ryunosuke Naito, Yuki Yoshioka, Mai Matsushita, Doi Nazuki and Nanako Watanabe

SPEAKERS:
Yuichiro Arima (Kumamoto University)
Nariko Arimura (Tohoku University)
Takayuki Hoshii (Chiba University)
Atsushi Iwama (University of Tokyo)
Makoto Makishima (Nihon University)
Kenichi Miharada (Kumamoto University)
Satoru Miyagi (Shimane University)
Goro Sashida (Kumamoto University)
Yorifumi Sato (Kumamoto University)
Toshio Suda (Kumamoto University)
Hitoshi Takizawa (Kumamoto University)
Takanori Teshima (Hokkaido University)
Hannah Uckelmann (Goethe University Frankfurt)
Satoshi Yamazaki (University of Tokyo)
Junichiro Yasunaga (Kumamoto University)
JSPS Core-to-Core Program A. Advanced Research Networks

Integrative approach for normal and leukemic stem cells

The 21st IRCMS Symposium on
The Dynamics and Development of Normal and Malignant Hematopoietic Stem Cells

Opening Remarks

Goro Sashida (IRCMS, Kumamoto University)

13:00-13:05

Session Ⅰ (13:05-14:30, 20th February)

Takayuki Hoshii
Chiba University

The SETD1B catalytic domain regulates H3K4me3 breadth and MYC
expression in MLL-rearranged leukemia

13:05-13:30

Targeting epigenetic vulnerabilities in acute myeloid leukemia

13:30-14:30

KeynoteHannah Uckelmann
Goethe University Frankfurt

Break (14:30-14:55)
thSessionⅡ (14:55-16:05 20 February)

Toshio Suda
Kumamoto University

Satoshi Yamazaki
University of Tokyo

Atsushi Iwama
University of Tokyo

Self-Renew Activity of Aging Hematopoietic Stem Cells

14:55-15:15

Establishment of absolute quantitative competitive hematopoietic stem cellfunction evaluation using X chromosome activation system

15:15-15:40

Targeting Hippo pathway in bone marrow niche promotes hematopoietic
regeneration

15:40-16:05

Break (16:05-16:30)
Session Ⅲ (17:00-17:45, 20th February)

Satoru Miyagi
Shimane University

Goro Sashida
Kumamoto University

Nariko Arimura
Tohoku University

Role of CUL4-RING E3 ubiquitin ligase complex in HSC fitness andhematopoiesis

16:30-16:55

Trisomy 21 represses expression of PRC2 targets and impairs
differentiation program in HSC

16:55-17:15

From Marrow to Memory: Tracing Dementia Onset using Down Syndrome
Model Mice

17:15-17:40

Session Ⅳ (9:00-10:30, 21st February)

Makoto Makishima
Nihon University

Kenichi Miharada
Kumamoto University

Yuichiro Arima
Kumamoto University

Regulation of hepatic immune cells by the oxysterol receptors, LXRs

9:00-9:25

Disruption of maternal bile acid metabolism causes non-fetal-autonomous
developmental defect

9:25-9:45

Protective Effects and Therapeutic Applications of Ketone Body
Metabolism in Liver

9:45-10:05

Break (10:05-10:25)
Session Ⅴ (10:25- 11:05, 21st February)

Yorifumi Sato
Kumamoto University

Junichiro Yasunaga
Kumamoto University

A human retrovirus inserts ectopic CTCF-binding site and enhancer into
the host human genome, thereby inducing aberrant host gene transcription
both in cis and in trans10:25-10:45

Coding and non-coding functions of HTLV-1 bZIP factor gene in the
oncogenesis of adult T-cell leukemia-lymphoma

10:45-11:05

Break (11:05-11:25)
Session Ⅵ (11:25-12:15, 21st February)

Hitoshi Takizawa
Kumamoto University

Takanori Teshima
Hokkaido University

Closiing Remarks

Microbial signal-regulated hematopoietic stem cell function

11:05-11:45

Alloreactive T-cell targets tissue stem cells and impairs tissue homeostasis
in GVHD after allogeneic stem cell transplantation

11:45-12:15

Hitoshi Takizawa (IRCMS, Kumamoto University)

JSPS Core-to-Core Program A. Advanced Research Networks

Integrative approach for normal and leukemic stem cells

12:15-12:20

The SETD1B catalytic domain regulates H3K4me3 breadth and MYC
expression in MLL-rearranged leukemia
Takayuki Hoshii(Chiba University)
Abstract :Histone H3 lysine 4 trimethylation (H3K4me3) is abundant in mixed-lineage leukemia-rearranged(MLL-r) acute myeloid leukemia (AML) cells; however, the enzymes responsible for this process
and their roles remain unclear. Therefore, this study aimed to identify the H3K4HMT modifier
responsible for high H3K4me3 modification in MLL-r leukemia and its downstream targets
essential for the cell proliferation. In the present study, we performed a CRISPR-tiling screen
against known H3K4 methylation modifiers in an MLL-r AML model. We elucidated the nonredundant roles of H3K4 methyltransferase SETD1B in regulating FLT3-ITD or NrasG12Dexpressing AML cell growth that exhibits cytokine-independent growth. Disrupting the SETD1B
catalytic SET domain caused cell cycle arrest, apoptosis, cell differentiation, and gene expression
downregulation, particularly in the MYC pathway. H3K4me3 and SETD1B are distributed in thegene body of MYC, and SETD1B SET domain loss results in a significant decrease in H3K4me3
breadth. Exogenous MYC expression significantly restored growth defects and transcriptional
perturbations in SETD1B SET domain-mutant cells. Disrupting H3K4 demethylase KDM5C
enhanced global H3K4me3 levels, promoted AML cell proliferation, and partially rescued thedefective cell growth of SETD1B SET domain-mutant cells. These data indicated that SETD1B was
required for H3K4me3 breadth and MYC expression to support advanced AML cell proliferation.
Thus, a thorough understanding of SETD1B-mediated H3K4me3 breadth is critical for developing
markers and therapies for MYC-dependent leukemia subtypes.
2-3 major papers:
1.
Perlee S, Kikuchi S, Nakadai T, Masuda T, Ohtsuki S, Matsumoto M, Rahmutulla B, Fukuyo
M, Cifani P, Kentsis A, Roeder RG, Kaneda A, *Hoshii T. SETD1A function in leukemia ismediated through interaction with mitotic regulators BuGZ/BUB3. EMBO Reports
24(10):e57108. (2023)
1.

*Hoshii T, Perlee S, Kikuchi S, Rahmutulla B, Fukuyo M, Masuda T, Ohtsuki S, Soga T, Nabet
B, Kaneda A. SETD1A regulates transcriptional pause release of heme biosynthesis genes inleukemia. Cell Reports 41(9):111727 (2022)

1.

Hoshii T, Cifani P, Feng Z, Huang CH, Koche R, Chen CW, Delaney CD, Lowe SW, Kentsis A,*Armstrong SA. A Non-catalytic function of SETD1A regulates Cyclin K and the DNA damage
response. Cell 172(5):1007-1021 (2018)

Bio:
Takayuki Hoshii obtained his Ph.D degree from Kumamoto University in 2007. As a postdoctoral
researcher, he studied on the roles of PI3K/AKT/mTOR signaling pathway in leukemogenesis. He
then joined the laboratory of Dr. Scott Armstrong at MSKCC and Dana-Farber Cancer Institute andfound the non-canonical role of SETD1A histone methyltransferase in leukemia. He came backJapan in 2019 and joined the Department of Molecular Oncology in Chiba University. His study
goal is to understand the biological roles of histone modification enzymes in leukemia and otherpediatric diseases associated with activation or mutation of these enzymes, and to identify
therapeutic potential functional domains.

Targeting epigenetic vulnerabilities in acute myeloid leukemia.

Hannah Uckelmann(Goethe University Frankfurt)
Abstract:
Cytoplasmic NPM1 mutations (NPM1c) in AML were first described almost two decades ago andrepresent one of the most frequently mutated genes in these leukemias. Much effort has been
focused on the cytoplasmic functions of mutant NPM1, however, its mechanistic role in leukemia
development remains elusive. Especially, how NPM1c expression in hematopoietic cells leads to
its characteristic gene expression pattern including many MLL target genes such as HOXA9 and
MEIS1. We have recently shown that NPM1c AMLs are highly sensitive to the disruption of theMLL1 histone methyltransferase complex. Small molecule inhibitors that block the interaction
between MLL1 and its adaptor protein Menin have been shown to impair binding of MLL1 to a
subset of its target genes and to inhibit leukemia cell proliferation and self renewal. The
effectiveness of these molecules in NPM1c AML prompts the question whether NPM1c and thewildtype MLL complex cooperate on chromatin. We now show that a small fraction of mutant
NPM1c is localized to the nucleus of leukemia cells where it regulates oncogenic transcription
directly on chromatin. We are now investigating the epigenetic complexes that are cooperatingwith NPM1c to drive leukemogenesis in order to identify novel therapeutic targets.
2-3 major papers:
Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid
leukemia.
Uckelmann HJ, Kim SM, Wong EM, Hatton C, Giovinazzo H, Gadrey JY, Krivtsov AV, Rücker FG,
Döhner K, McGeehan GM, Levine RL, Bullinger L, Vassiliou GS, Armstrong SA.
Science, 2020.
Mutant NPM1 directly regulates oncogenic transcription in acute myeloid leukemia.
Uckelmann HJ#, Haarer EL, Takeda R, Wong EM, Perner F, Marinaccio C, Hatton C, Yang L,
Brunetti L, Chen CW, Armstrong SA#. #Co-corresponding authors.
Cancer Discovery, 2023.
Bio:
Dr. Hannah Uckelmann’s research group focuses on studying the epigenetic regulation of selfrenewal programs during cancer development and the discovery of new therapeutics. Dr.
Uckelmann received her master’s degree in Molecular Biosciences from the university of
Heidelberg and her PhD with Prof. Andreas Trumpp at the German Cancer Research Center(DKFZ) in Heidelberg. For her postdoctoral training, Dr. Uckelmann joined the group of Prof. Scott
Armstrong at the Dana-Farber Cancer Institute in Boston. She was able to show that disrupting
the MLL-complex on chromatin using Menin-MLL inhibitors can prevent the development ofleukemia in NPM1c-mutant mouse models and treat fully developed human leukemias derived
from patient samples. This preclinical work led to the inclusion of NPM1 mutant patients in theongoing clinical phase II trials for Menin-MLL inhibitors.

Self-Renew Activity of Aging Hematopoietic Stem Cells

Toshio Suda
(Kumamoto University)
Abstract:
It has been previously reported several findings regarding aged hematopoietic ＨＳＣｓ, showing:i)a decline in self-renewal capacity (an increase in cells with stem cell markers),ii)
an increase in oxidative phosphorylation in stem cell mitochondria,iii) a reduction in quiescent stem cells.
We have conducted RNAseq and ATACseq analyses of aged hematopoietic stem cells (HSCs). In
aging stem cells, gene expression suggests differentiation towards progenitors. and we can also
capture aging-related gene changes specific to HSCs. Under the hypothesis that "Aging leads to anenrichment of stem cells with self-renewal advantage genes," we try to identify candidate genes:
It is important to use the common phenotype of HSCs between young and aged HSCs, sincesome HSC phenotypes are changing by aging. To aim to define HSCs having self-renewal capacity
during life span, we have recently provided novel insights into transplantable HSCs during
regeneration of hematopoiesis. HSCs highly expressing EPCR (EPCR-high) cells are enriched within
the stem cell fraction at the expense of more proliferative EPCR-low HSCs. We have concluded
EPCR-high HSCs are initially more primitive than EPCR-low HSCs and enabled stem cell expansion.
Moreover, we have recently discovered that aging stem cells with a higher quantity of
mitochondria (MitoH) persist in the bone marrow. We will clarify how MitoH HSCs canpreferentially survive and show the fitness with aged bone marrow.
2-3 major papers:
1.

Umemoto T, Johansson A, Ahmad SAI, Hashimoto M, Kubota S, Odaka H, Kataoka M, Era T,
Sashida G, Suda T: The suppression of reductive glutamine metabolism is required topreserve stem cell features in primed hematopoietic stem cells. EMBO J. 2022 Apr
19;41(8):e109463. doi: 10.15252/embj.2021109463.

2.

Yokomizo T, Ideue, T, Sato T, Takeda N,Kurokawa M, Komatsu N, Araki, K, Osato M, Suda T:
Independent origins of fetal liver hematopoietic stem and progenitor cells. Nature,Sep;609(7928):779-784. doi: 10.1038/s41586-022-05203-0.

3.

Yang C, Yokomori R, Chua LH, Tan SH, Sanda T, Suda T; Mitochondria transfer mediates
stress erythropoiesis by altering the bioenergetic profiles of early erythroblasts throughCD47. J Exp Med, 2022 Dec5;219(12): e20220685. doi: 10.1084/jem.20220685

Bio:
Toshio Suda has studied hematopoietic stem cells (HSCs) and HSC niches for over forty years.
His past work encompasses the purification of HSCs, identification of cytokine signaling inhematopoiesis, and the characterization of HSC niches in bone marrow. Although stem cells
differentiate along with a cell autonomous intrinsic program, this process is influenced by the
microenvironment of the stem cells niche. He identified the endosteal niche for HSC niche,and subsequently established the new field of oxidative stress and stem cell aging.

Establishment of absolute quantitative competitive hematopoietic stem
cell function evaluation using X chromosome activation system
Satoshi Yamazaki(University of Tokyo)
Abstract:
Hematopoietic stem cells (HSCs) are one of the most well-studied adult stem cell populations andhave provided many important concepts in the field of stem cell biology. HSCs are a rare cell
population found within the bone marrow (BM) with remarkable functional capabilities ofmultilineage differentiation and lifelong self-renewal. To date, competitive bone marrow
repopulation assays have been used as the gold standard to analyze the molecular mechanisms
underlying the functional capacity of HSCs. Generally, competitive bone marrow reconstitution
assays involve irradiating the recipient mouse with a lethal dose of radiation, which induces
strong inflammation in the body. Analysis of wild-type HSCs in a steady state and essentiallycompetitive hematopoietic stem cells with forced expression or deletion of specific genes due toin vivo inflammatory exposure has not yet been established. In contrast to HSCs, many other
adult stem cell populations have successfully verified their steady state stemness through in vivo
genetic lineage tracing approaches rather than transplantation assays. Intestinal stem cell analysis
using genetic lineage tracing of Lgr5 expression with the Cre/LoxP recombination system has beenreported in the most successful cases. In the blood field, experimental systems have been
established for the purpose of marking and tracing HSC-specific genes. However, there was noexperimental system that competitively compared the wild-type group and the control group
without using an experimental system called transplantation. In this Symposium, I will introduce acompetitive phenotypic analysis method for HSCs based on the X-chromosome inactivation
system that I devised and discuss the absolute quantitative competitive cell comparison method
and the interesting aspects of biology that I have learned through this research.

2-3 major papers:
1.
Tajima et al., 2017 Scientific Reports
Bio :Yamazaki is a researcher who aims to make ex vivo expansion of hematopoietic stem cells
possible and further uncover the mysteries of stem cells.

Targeting Hippo pathway in bone marrow niche promotes hematopoietic
regeneration
Atsushi Iwama(University of Tokyo)
Abstract:
The distinctive milieu of bone marrow (BM), called a "niche”, supports hematopoietic stem cells(HSCs) and serves as the foundation of hematopoietic regeneration. Myeloablative stress disrupts
not only hematopoietic cells but also niche components, including endothelial cells (EC) andmesenchymal stromal cells (MSC), which hinders efficient hematopoietic recovery. YAP/TAZ are
the two transcriptional coactivators repressed by LATS1/2 kinases downstream of the Hippo
pathway essential for regeneration of various organs. However, their role in hematopoietic
regeneration remained uncharacterized. Here we show that LATS inhibition promotes remodelingof damaged BM niche, thereby promoting hematopoietic regeneration in mice. We revealed that
YAP/TAZ are selectively expressed in ECs and MSCs in BM and are activated by myeloablative
genotoxic stresses. Administration of newly developed LATS inhibitors, which efficiently activated
YAP/TAZ in niche cells, profoundly accelerated hematopoietic recovery by host cells after
myeloablative stresses as well as by donor HSCs in a transplantation model, which wassignificantly canceled by deletion of Yap and Taz in BM niche cells. Combination of granulocytecolony-stimulating factor (G-CSF) and LATS inhibitors established significantly earlier recovery ofneutrophils than G-CSF alone. These results provide the first evidence of successful manipulationof BM niche cells to boost hematopoietic recovery after myeloablation.
2-3 major papers:
1.
Itokawa N, Oshima M, Koide S, Takayama N, Kuribayashi W, Nakajima-Takagi Y, Aoyama K,
Yamazaki S, Yamaguchi K, Furukawa Y, Eto K, Iwama A. Epigenetic memories inscribed inchromatin accessibility in aged hematopoietic stem cells. Nat Commun 13(1): 2691, 2022.
2.
Kuribayashi W, Oshima M, Itokawa N, Koide S, Nakajima-Takagi Y, Yamashita M, Yamazaki
S, Rahmutulla B, Miura F, Ito T, Kaneda A, and Iwama A. Limited rejuvenation of aged
hematopoietic stem cells in young bone marrow niche. J Exp Med 218(3):e20192283,
2021.
3.
Miyagi S, Sroczynska P, Kato Y, Nakajima-Takagi Y, Oshima M, Rizq O, Takayama N, Saraya
A, Mizuno S, Sugiyama F, Takahashi S, Matsuzaki Y, Christensen J, Helin K, and Iwama A.
The chromatin binding protein Phf6 restricts the self-renewal of hematopoietic stem cells.
Blood 133(23):2495-2506, 2019.
Bio:
Atsushi Iwama is a professor of the Institute of Medical Science, the University of Tokyo. He
obtained his M.D. in Niigata University and Ph.D. in Kumamoto University in 1987 and 1996,
respectively. He completed an internship and residency at Niigata University Hospital and Jichi
Medical School Hospital, respectively. Originally starting his training in clinical hematology, he has
specialized in research on hematopoietic stem cells (HSCs) and hematological malignancies. He
became independent as a full professor at the Graduate School of Medicine, Chiba University in2005 and carried out research on the epigenetic regulation of HSCs and the epigenetic
dysregulation in hematological malignancies.. From March 2018, he has been appointed as aprofessor at the current institute and is expanding his research field to HSC aging.

Role of CUL4-RING E3 ubiquitin ligase complex in HSC fitness andhematopoiesis
Satoru Miyagi(Shimane University)
Abstract :Inactivation of chromatin modifier genes, e.g., Tet2, Dnmt3a, or Asxl1, augments thereconstitution activity of hematopoietic stem cells (HSCs) in the transplantation setting. The
inactivation of Tet2 (or Dnmt3a) shows divergent effects on HSCs. For instance, the lossof Tet2 improves the fitness of HSCs in an inflammatory microenvironment in addition to HSC
proliferation; therefore, Tet2 loss confers a competitive advantage on HSCs.
PHF6, which frequently acquires inactivating somatic mutations in various hematologicalmalignancies, is a critical negative regulator of HSCs in stress hematopoiesis. Molecularly, PHF6
regulates gene expression by modifying higher-order chromatin structure. Our previous study
demonstrated that PHF6 binds to the downstream effector gene locus of TNFα signaling, including
tumor suppressor genes Nr4a1 and Junb, and activates their transcription in a TNFα-dependent
manner. Thus, Phf6-deficient HSCs show a competitive advantage.
Recently, we found that the PHIP/DCAF14, the substrate receptor subunit of the CUL4-RING E3
ubiquitin ligase complex (CRLc), is a putative binding partner of PHF6 and PHIP overexpression
enhances the mono-ubiquitination of PHF6.
The CRLc-mediated mono-ubiquitination takes part in the recruitment of Tet2 on chromatin, andTNFα signaling increases the expression and enzymatic activity of CRLc. In my presentation, I will
discuss the role of CRLc in HSC fitness and hematopoiesis.
2-3 major papers:
1. Miyagi S, Sroczynska P, Kato Y, Nakajima-Takagi Y, Oshima M, Rizq O, Takayama N, Saraya A,
Mizuno S, Sugiyama F, Takahashi S, Matsuzaki Y, Christensen J, Helin K, Iwama A. The
chromatin-binding protein Phf6 restricts the self-renewal of hematopoietic stem cells. Blood.
133, 2495-2506, 2019.
2. Miyagi S, Iwama A. Plant homeodomain finger protein 6 in the regulation of normal andmalignant hematopoiesis. Curr Opin Hematol. 27, 248-253. 2020.
3. Miyagi S*, Kato Y, Watanabe A, Miyamoto K, Yoshikawa R, Hagiya K, Hirano D, Matsuzaki Y*.
Generation of a BAC transgenic mouse strain that expresses CreERT and a fluorescent protein
under the transcriptional control of the Fzd5 locus. Inflamm. Regen. 42, 2022.
Bio:
I received my Ph.D. from the United Graduate School of Agricultural Sciences, Iwate University(UGAS), Japan, and have expertise in Stem Cell Biology, Molecular Biology, and Biochemistry.
After post-doctoral training, I joined Dr. Iwama's lab and have dedicated my academic career tothe basic research of hematopoietic stem cells. My research aims to develop new therapeuticstrategies to prevent and cure hematological malignancies. My current research focuses on thesomatic mutation of the genes that encode chromatin modifiers to elucidate the mechanisms
underlying the onset of hematological malignancies. I am setting up my lab at the Faculty of
Medicine at Shimane University.

Trisomy21 represses expression of PRC2 targets and impairs differentiation
program in HSC
Goro Sashida(Kumamoto University)
Abstract:
Down syndrome (DS) human show chronic diseases including premature aging phenotypes inblood and brain tissues. Aged hematopoietic stem cells (HSCs) decrease the regenerative capacityand promote myeloid differentiation. Although DS HSC is known to drive aging phenotypes, themolecular mechanisms underlying premature aging is unclear. By using a mouse model TcMAC21,
we herein demonstrated that DS mice showed reduced regenerative capacity and myeloid
skewing in bone marrow (BM). To determine the intrinsic and extrinsic effects, BM cells from
DS/WT mice were transplanted into wild-type recipients, and BM cells from WT mice weretransplanted into DS/WT recipients. We found the impaired function of HSC in the DS-BM
transplanted WT mice, whereas the WT-BM transplanted DS mice showed mild myeloid skewing
but did not impair the HSC function. Transcriptome analysis revealed that the DS-HSC decreased
expression levels of stem cell signature genes and polycomb repressive complex 2 (PRC2)-target
genes. In addition, level of cytosine DNA methylation was increased in DS mice, accompaniedwith reduced expression of the Tet2 gene. Since canonical PRC2 targets are shown to gain DNA
methylation at their CpG sites in aged cells, our results suggested that DS HSCs accelerated
epigenetic aging in the cell-intrinsic manner. Further studies are needed to clarify themechanisms by which epigenetic alterations affects the age-related diseases in DS HSC.

2-3 major papers:
1.
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. J Exp Med 2023; 220(7): e20220962.
2.
Abdallah MG, Niibori-Nambu A, Morii M, Yokomizo T, Yokomizo T, Ideue T, Kubota S, Teoh
VSI, Mok MMH, Wang CQ, Omar AA, Tokunaga K, Iwanaga E, Matsuoka M, Asou N,
Nakagata N, Araki K, AboElenin M, Madboly SH, Sashida G*, Osato M*. RUNX1-ETO(RUNX1-RUNX1T1) induces myeloid leukemia in mice in an age-dependent manner.
Leukemia 2021. 35(10): 2983-2988.
3.
Kubota S, Tokunaga K, Umezu T, Yokomizo-Nakano T, Sun Y, Oshima M, Tan KT, Yang H,
Kanai A, Iwanaga E, Asou N, Maeda T, Nakagata N, Iwama A, Ohyashiki K, Osato M*,
Sashida G*. Lineage-specific RUNX2 super-enhancer activates MYC and promotes thedevelopment of blastic plasmacytoid dendritic cell neoplasm. Nature Commun 2019; 10(1):
1653.
Bio:
Goro Sashida recieved his MD from Tokyo Medical University in 1996. In 2005, he joined Dr.
Stephan Nimer's laboratory at Memorial Sloan-Kettering Cancer Center (New York, USA; Dr.
Nimer moved to Miami). In 2009, he moved to Dr. Gang Huang's laboratory at Cincinnati
Children's Hospital Medical Center (Ohio, USA; Dr Huang moved to San Antonio). In 2010, he
went back to Japan and joined Dr. Atsushi Iwama's laboratory at Chiba University (Chiba, Japan;
Dr. Iwama moved to Tokyo). In December 2014, he established his own research group"Laboratory of Transcriptional Regulation of Leukemogenesis" at IRCMS, Kumamoto University,and in 2016 he was promoted to Professor.

From Marrow to Memory: Tracing Dementia Onset using Down Syndrome
Model Mice
Nariko Arimura(Tohoku University)
Abstract:
Dementia refers to the gradual loss of cognitive function due to various factors affecting thebrain. Alzheimer's disease is estimated to cause two-thirds of all cases of dementia, but the initial
triggers for the onset of the disease are still unknown. Down syndrome is attracting attention as amodel for dementia because almost all patients with Down syndrome develop early-onset
Alzheimer's disease. People with Down syndrome frequently exhibit immune systemdysfunctions, which are increasingly recognized as being linked to neurodegenerative diseases. In
light of this, we have initiated a focused investigation into the interplay between dementia andimmune cell activity. Behavioral analysis was conducted in wild-type mice transplanted with bonemarrow from Down syndrome model mice, and the transplanted mice showed reduced cognition
and memory. We have found an increase or decrease in a specific population of neurons basedon genetic and immunohistochemical analysis of the hippocampus, the center of memory. These
results indicate that bone marrow-derived cells and blood components influence brain function.
We are currently investigating how bone marrow-derived components of Down syndrome affectthe brain through the blood-brain barrier. In this symposium, we will describe the results of ourexperiments and discuss new light on the therapeutic use of blood components in treating
dementia.
2-3 major papers:
1. A Comparative Overview of DSCAM and its Multifunctional Roles in Drosophila andVertebrates Kento Hizawa, Takuya Sasaki, Nariko Arimura* Neuroscience Research, in press.
2. Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia forfunctional synapse formation. Ken-ichi Dewa, Nariko Arimura*, Wataru Kakegawa, Masayuki
Itoh, Toma Adachi, Satoshi Miyashita, Yukiko U. Inoue, Kento Hizawa, Kei Hori, Natsumi
Honjoya, Haruya Yagishita, Shinichiro Taya, Taisuke Miyazaki, Chika Usui, Shoji Tatsumoto,
Akiko Tsuzuki, Hirotomo Uetake, Kazuhisa Sakai, Kazuhiro Yamakawa, Takuya Sasaki, Jun
Nagai, Yoshiya Kawaguchi, Masaki Sone, Takayoshi Inoue, Yasuhiro Go, Noritaka Ichinohe,
Kozo Kaibuchi, Masahiko Watanabe, Schuichi Koizumi, Michisuke Yuzaki, Mikio Hoshino*
Nature Communication, in press.
3. DSCAM regulates delamination of neurons in the developing midbrain. Nariko Arimura*,
Mako Okada, Shinichiro Taya, Ken-ichi Dewa, Akiko Tsuzuki, Hirotomo Uetake, Satoshi
Miyashita, Koichi Hashizume, Kazumi Shimaoka, Saki Egusa, Tomoki Nishioka, Yuchio
Yanagawa, Kazuhiro Yamakawa, Yukiko U. Inoue, Takayoshi Inoue, Kozo Kaibuchi, Mikio
Hoshino* Science Advances, 6(36) eaba1693-eaba1693, 2020.
Bio:
I am an Associate Professor specializing in neuroscience at the Graduate School of Pharmaceutical
Sciences, Tohoku University. My interest particularly lies in the control systems of cognition andmemory and the dynamics of neural circuits. My research has utilized molecular biology, genetics,
and cerebral physiology techniques to gain a multidimensional understanding of brain function,
aiming to contribute to the elucidation of pathological states. At this symposium, I will discuss thefunctional control of the brain exerted by Down syndrome marrow and plan to present on the
exploration of the molecular mechanisms involved in the onset of dementia.

Regulation of hepatic immune cells by the oxysterol receptors, LXRs
Makoto Makishima(Nihon University)
Abstract:
Transcription factors of the nuclear receptor superfamily regulate numerous biological processes
including cell growth and differentiation, embryonic development, endocrine regulation, andmetabolic homeostasis. The nuclear receptors liver X receptor α (LXRα) and LXRβ are activated byoxysterols and regulate expression of genes involved in lipid metabolism. LXRα is abundantly
expressed in liver, intestine, adipose tissues, kidney and macrophages, while LXRβ is ubiquitously
present in the body. LXRs also regulate immune responses in immune cells, such as macrophages,
and induction of genes involved in reverse cholesterol transport. In the liver, LXRs are expressedin both hepatocytes and nonparenchymal cells, including leukocytes, hepatic stellate cells, andliver sinusoidal endothelial cells. Since the liver plays important roles in both lipid metabolism andinnate immunity as a gateway for dietary compounds, LXRs are suggested to have a gatekeeper
function in the liver. We investigated the role of LXRs in hepatic immune cells using LXRα/βknockout (KO) mice. LXRα/β-KO mice show increased numbers of F4/80loCD11b+ macrophages in
the liver and enhanced inflammatory responses. Hepatic invariant natural killer T cells are nearly
absent in the liver of LXRα/β-KO mice. Thus, LXRs play an important role in regulation of hepatic
macrophages/Kupffer cells and natural killer T cells.

2-3 major papers:
1.
Endo-Umeda, et al. Liver X receptors regulate natural killer T cell population and antitumor
activity in the liver of mice. Sci Rep 11: 22595, 2021
2.
Endo-Umeda, et al. Liver X receptors regulate hepatic F4/80+CD11b+ Kupffer
cells/macrophages and innate immune responses in mice. Sci Rep 8: 9281, 20183.
Endo-Umeda, et al. Dysregulation of Kupffer cells/macrophages and natural killer T cells insteatohepatitis in LXRα knockout male mice. Endocrinology 159: 1419, 2018
Bio:
Dr. Makoto Makishima graduated from National Defense Medical College in 1987. While working
as a physician at Ground Self Defense Force and Saitama Comprehensive Mental Health Center,
he did research studies at Saitama Cancer Center and received PhD in Medical Science from Jichi
Medical University. He joined David Mangelsdorf laboratory at University of Texas Southwestern
Medical Center as Associate of Howard Hughes Medical Institute from 1998 to 2002, andreported two papers about bile acid receptors in Science. He worked at Osaka University as
Associate Professor from 2002 to 2004. Since 2004, he has been at Nihon University School of
Medicine, where he currently is Professor of the Division of Biochemistry, Director of Library andDirector of Research Institute of Medical Science. His research team is mainly focused on nuclear
receptor regulation of metabolism and immunity.

Disruption of maternal bile acid metabolism causes non-fetal-autonomous
developmental defectKenichi Miharada(Kumamoto University)
Abstract:
The importance of the maternal environment for fetuses has undoubtedly been described.
However, how molecularly maternal metabolism contributes to fetal organ maturation remains
unclear. Bile acids are major cholesterol derivatives whose synthesis is enhanced in mothers;
however, their role in fetal development has been undiscovered. Here, we demonstrate that thealternative pathway of bile acid synthesis in maternal bodies secures progression of normal fetalorgan formation by assuring a translation machinery. Depletion of maternal Cyp27a1 leads to avariety of abnormal pregnancy outcomes. These are caused by accumulating intermediate
product, 7α-hydroxycholesterol (7α-HC), that destabilized the Fau protein mediating ribosome
assembly. Aberrant ribosome biogenesis results in inefficient translation of proteins essential forcellular and organ maturation. Thus, our study indicates that an essential mechanism of securing
fetal development by degrading a toxic metabolite in the maternal body.
2-3 major papers:
1.
Suzuki M, Nakano S, Miharada N, Takei H, Prabhala P, van der Garde M, Müller C,
Sigurdsson V, Aerken M, Saito K, Koide S, Westergren-Thorsson G, Magnusson M, Kakiyama
G, Nittono H, Miharada M*. Maternal sterol 27-hydroxylase is crucial for securing fetal
development. bioRxiv 2023.11.08.566330.
1.

Sigurdsson V, Haga Y, Takei H, Mansell E, Okamatsu-Haga C, Suzuki M, Radulovic V, van der
Garde M, Koide S, Soboleva S, Gåfvels M, Nittono H, Ohara A, Miharada K*. Induction ofblood-circulating bile acids supports recovery from myelosuppressive chemotherapy. Blood
Adv. 2020 May 12;4(9):1833-1843.

1.

Sigurdsson V, Takei H, Soboleva S, Radulovic V, Galeev R, Siva K, Leeb-Lundberg LMF, Iida T,
Nittono H, Miharada K*. Bile acids protect expanding hematopoietic stem cells from
unfolded protein stress in fetal liver. Cell Stem Cell 2016 Apr 7;18(4):522-32

Bio:
Kenichi Miharada, Ph.D, obtained his Ph.D degree from Tsukuba University, Japan, in 2007 for his
studies on erythropoiesis. He continued his research at RIKEN as a Special Postdoctoral
Researcher and then moved to Lund University, Sweden, in 2009. At Lund Stem Cell Center, he
led projects discovering novel HSC regulators. In 2013, he started his research group as a principal
investigator (PI) at Lund Stem Cell Center to study the regulation of UPR in HSC. Since 2021, hehas become a member of IRCMS as a professor and started a new lab. Dr. Miharada aims to build
novel concepts by exploring unexpected connections between various findings.

Protective Effects and Therapeutic Applications of Ketone Body
Metabolism in Liver
Yuichiro Arima(Kumamoto University)
Abstract:
Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic
byproducts known as energy substrates during fasting. Recent advancements have shed light on
the multifaceted effects of ketone body metabolism, leading to increased interest in therapeuticinterventions aimed at elevating ketone body levels. However, excessive elevation of ketone bodyconcentration can lead to ketoacidosis, which may have fatal consequences. Therefore, our main
purpose is to decipher the precise role of ketone body metabolism, particularly emphasizing its
association with mitochondria and epigenetic modification. Metabolic dysfunction associatedfatty liver disease (MAFLD) has been on the increase worldwide due to the increase in thenumber of patients with obesity and metabolic syndrome. Lifestyle factors such as diabetes andobesity are major causes of the disease, and MAFLD has the risk of progressing to nonalcoholicsteatohepatitis (NASH), as well as cirrhosis and hepatocarcinoma. Previously, we have generated
the murine model of insufficient ketogenesis by disrupting the rate-limiting enzyme for
ketogenesis, HMG-CoA synthase 2 (Hmgcs2) and reported that ketogenesis regulated lipid
homeostasis in hepatocytes in neonate. In this presentation, we provide the impact of ketone
body metabolism in adult MAFDL models.
2-3 major papers:
1.
Wenjuan Ma, Yuichiro Arima, Terumasa Umemoto, Tomomasa Yokomizo, Yuqing Xu,
Kenichi Miharada, Yosuke Tanaka, Toshio Suda. Metabolic regulation in erythroid
differentiation by systemic ketogenesis in fasted mice. Experimental hematology 2023 inpress
2.
Yuichiro Arima. The Impact of Ketone Body Metabolism on Mitochondrial Function andCardiovascular Diseases. Journal of atherosclerosis and thrombosis 30(12) 1751-1758 2023
(review)
3.
Yuichiro Arima, Yoshiko Nakagawa, Toru Takeo, Toshifumi Ishida, Toshihiro Yamada,
Shinjiro Hino, Mitsuyoshi Nakao, Sanshiro Hanada, Terumasa Umemoto, Toshio Suda,
Tetsushi Sakuma, Takashi Yamamoto, Takehisa Watanabe, Katsuya Nagaoka, Yasuhito
Tanaka, Yumiko K Kawamura, Kazuo Tonami, Hiroki Kurihara, Yoshifumi Sato, Kazuya
Yamagata, Taishi Nakamura, Satoshi Araki, Eiichiro Yamamoto, Yasuhiro Izumiya, Kenji
Sakamoto, Koichi Kaikita, Kenichi Matsushita, Koichi Nishiyama, Naomi Nakagata, Kenichi
Tsujita. Murine neonatal ketogenesis preserves mitochondrial energetics by preventing
protein hyperacetylation. Nature metabolism 3(2) 196-210 2021

Bio:
Yuichiro Arima is an associate professor in the developmental cardiology laboratory of theInternational Research Center for Medical Siences (IRCMS) at Kumamoto University. He is aphysician-scientist and has a keen interest in the relationship between cardiovasculardevelopment and pathology, and ketone body metabolism. He is trying to clarify the relationshipbetween cardiovascular development and adult-onset disease through basic research. In addition,in the process of analyzing the neonatal period, he elucidated the significance of ketone bodymetabolism, by analyzing the knockout (KO) mice for HMG-CoA synthase2 (Hmgcs2), the ratelimiting enzyme in ketone body synthesis. Hmgcs2 KO mice can survive but represent severe
hepatostetosis with mitochondrial dysfunction. He has deciphered the underlying mechanism andrevealed that ketogenesis itself has a protective function for mitochondria. Multifaced functionsof ketone body metabolism is an important theme for his research.

A human retrovirus inserts ectopic CTCF-binding site and enhancer into thehost human genome, thereby inducing aberrant host gene transcription
both in cis and in trans
Yoshifumi Sato
(Kumamoto University)
Abstract:
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes adult T-cellleukemia/lymphoma (ATL), a cancer of infected CD4+ T cells. There is both sense and antisensetranscription from the integrated provirus. Sense transcription tends to be suppressed, butantisense transcription is constitutively active. Since HTLV-1 integrates and forms proviral DNA in
the host genome, there should be some interaction between the proviral DNA and the hostgenome.
We previously reported that CTCF, a key regulator of chromatin structure and function, binds tothe provirus at a sharp border in epigenetic modifications in the pX region of the HTLV-1 provirus(1). CTCF is a zinc-finger protein that binds to an insulator region in genomic DNA and plays afundamental role in controlling higher order chromatin structure and gene expression invertebrate cells. We additionally found a previously unidentified viral enhancer in the middle ofthe HTLV-1 provirus (3). HTLV-1 generates an ectopic enhancer region in addition to the viral
CTCF insulator region. These findings indicate that the HTLV-1 enhancer can induce a distinct
alteration of the host transcriptome via chromatin looping, and thereby upregulates cancerrelated genes near viral integration sites which might contribute to the preferential selection of a
specific infected cell for clonal expansion during the early phase of leukemogenesis.

2-3 major papers:
1.
Satou Y*, Miyazato P, Ishihara K, Yaguchi H, Melamed A, Miura M, Fukuda A, Nosaka K,
Watanabe T, Rowan A, Nakao M, and Bangham CRM*. The retrovirus HTLV-1 inserts anectopic CTCF-binding site into the human genome. PNAS 113: 3054-59, 2016.
2.
Tan B, Sugata K, Reda O, Matsuo M, Uchiyama K, Miyazato P, Hahaut V, Yamagishi M,
Uchimaru K, Suzuki Y, Ueno T, Suzushima H, Katsuya H, Tokunaga M, Uchiyama Y,
Nakamura H, Sueoka E, Utsunomiya A, Ono M* and Satou Y*. HTLV-1 infection promotes
excessive T cell activation and transformation into adult T cell leukemia/lymphoma. JCI,
131(24):e150472, 2021
3.
Matsuo M, Ueno T#, Monde K#, Sugata K#, Miyazato P, Tan B, Rahman A, Islam S, Katsuya H,
Nakajima S, Tokunaga M, Nosaka K, Hata H, Utsunomiya A, Fujisawa J, and Satou Y*.
Identification and characterization of a novel enhancer in the HTLV-1 proviral genome. Nat
Comm 13(1):2405, 2022.

Bio:
During my PhD course I carried out studies on novel treatment of ATL (Leukemia 2004). As a post
doctorial study, I analyze antisense viral gene HBZ about expression and role in HTLV-1
pathogenesis by using clinical samples and transgenic mouse model (PNAS 2006, PLoS Pathogens2011). I then performed molecular biology experiment to elucidate the mechanism underlying
retroviral latency (PNAS 2016). Since I obtained PI position in 2013, I have incorporated highthrough-put sequencing technology as a tool to understand genetic and epigenetic regulatory
mechanism of retroviral latency regarding both HTLV-1 and HIV-1 (Cell Rep 2019, JCI 2021, Nat
Commun 2022).

Coding and non-coding functions of HTLV-1 bZIP factor gene in the
oncogenesis of adult T-cell leukemia-lymphoma
Junichiro Yasunaga(Kumamoto University)
Abstract:
Adult T-cell leukemia-lymphoma (ATL) is a malignancy of mature CD4+ T cells induced by humanT-cell leukemia virus type 1 (HTLV-1). HTLV-1 maintains a life-long infection in vivo mainly byclonal proliferation of infected cells. Among viral genes encoded in the HTLV-1 provirus, only
HTLV-1 bZIP factor (HBZ) is conserved and expressed in all ATL cases. Knock down of HBZ
suppresses the proliferation of ATL cell lines, indicating that HBZ is critical for the proliferationand maintenance of ATL. HBZ is a unique gene which transcript not only encodes HBZ protein but
also acts like long non-coding RNAs. Recently, we reported that both HBZ RNA and HBZ protein
upregulate a cellular gene TAp73 in different manners. Consequently, TAp73 contributes to boththe Warburg effect and epigenetic reprogramming in HTLV-1–infected cells via induction of
MCT1/4 and EZH2, respectively. It is also found that nuclear localization of HBZ RNA and HBZ
protein is associated with their oncogenic properties. The former is regulated by the activation of
the 3’LTR, which is a promoter of HBZ gene, and the latter is accelerated by the TGF-beta/Smadpathway. These multimodal functions of HBZ are thought to be critical for the leukemogenesis ofATL.
2-3 major papers:
1.
Toyoda K, Yasunaga JI, Shichijo T, Arima Y, Tsujita K, Tanaka A, Salah T, Zhang W, Hussein O,
Sonoda M, Watanabe M, Kurita D, Nakashima K, Yamada K, Miyoshi H, Ohshima K and
Matsuoka M. HTLV-1 bZIP factor-induced reprogramming of lactate metabolism andepigenetic status promote leukemic cell expansion. Blood Cancer Discov, 2023; 4: 374-393.
2.
Ma G, Yasunaga JI, Shimura K, Takemoto K, Watanabe M, Amano M, Nakata H, Liu B, Zuo X,
Matsuoka M. Human retroviral antisense mRNAs are retained in the nuclei of infected cells
for viral persistence. Proc Natl Acad Sci USA, 2021; 118: e2014783118.
3.
Higuchi Y, Yasunaga JI, Mitagami Y, Tsukamoto H, Nakashima K, Ohshima K, and Matsuoka
M. HTLV-1 induces T-cell malignancy and inflammation by viral antisense factor-mediatedmodulation of the cytokine signaling. Proc Natl Acad Sci U S A, 2020; 117:13740-13749.

Bio:
2003-2007 Assistant professor at Institute for Virus Research, Kyoto University
2007-2010 Visiting fellow at National Institute of Allergy and Infectious Diseases, National
Institutes of Health, United states
2010-2019 Lecturer at Institute for Virus Research, Kyoto University
2019-2023 Associate professor at Departments of Hematology, Rheumatology and Infectious
Disease, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto
University
2024Professor at Departments of Hematology, Rheumatology and Infectious Disease,
Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto
University

Microbial signal-regulated hematopoietic stem cell function

Hitoshi Takizawa(Kumamoto University)
Hematopoiesis is a continuous blood production that is sustained by hematopoietic stem cells(HSCs), a somatic stem cell that lifelong selfrenew and differentiate into all blood and immune
cells. When hematopoietic stress such as infection, inflammation, chemotherapy occur, HSC andprogenitor function substantially change, i.e., attenuate HSC selfrenewal, bias their differentiation
potential, etc. We have studied a role of innate immune signaling in HSCs and their offspring in
the context of infection, inflammation and leukemogenesis. In this lecture, I would like to show
recent findings in the field of stress hematopoiesis and discuss how to extrapolate its role fordevelopment and maintenance of hemato-immune system throughout various lifetime events
including development, aging and cancer.
2-3 major papers:
1.
Wang Y, Morishima T, Sezaki M, Sato R, Nakato G, Fukuda S, Kobiyama K, Ishii KJ, Li Y,
Takizawa H. Akkermansia muciniphila induces slow extramedullary hematopoiesis via
cooperative IL-1R/TLR signals. EMBO Rep., 2023 Dec 6;24(12):e57485. doi:
10.15252/embr.202357485. Epub 2023 Oct 23.
2.
Sezaki M, Hayashi Y, Nakato G, Wang Y, Nakata S, Biswas S, Morishima T, Fakruddin M,
Moon J, Ahn S, Kim P, Miyamoto Y, Baba H, Fukuda S, Takizawa H. Hematopoietic stem andprogenitor cells integrate microbial signals to promote post-inflammation gut tissue repair.
EMBO J., 2022 Oct 18;e110712.
3.
Takizawa H(co-corespondance), Fritsch K, Kovtonyuk LV, Saito Y, Yakkala C, Jacobs K, Ahuja
AK, Lopes M, Hausmann A, Hardt WD, Gomariz Á, Nombela-Arrieta C and Manz MG.
Pathogen-induced TLR4-TRIF innate immune signaling in hematopoietic stem cells promotes
proliferation but reduces competitive fitness. Cell Stem Cell., 2017 Aug 3;21(2):225-240.
doi: 10.1016/j.stem.2020.06.010.
Bio (About 100words is preferred):
I have been specialized in stem cell biology with strong interest and focus on inflammatorystress. Early on, I studied cytokine signallings through c-Kit and c-Mpl for HSC expansion andmaintenance (Blood 2006; JCI 2010, Blood 2016). Then, my work was shifted toward
understanding of HSC cycling dynamics in a steady state and inflammatory context such as
infection, leukemogenesis (JEM 2011, JEM 2014, Cancer Sci 2022). I found that HSCs can sense
infection-associated danger signals through toll-like receptor 4 to adapt hematopoiesis into hostdefense enhancement (Blood 2012, JEM 2011, Cell Stem Cell 2017). More recently, I showed
microbiota penetrating through gut upon inflammation or aging affect HSC function (Blood
2022, EMBO J 2022, EMBO Rep 2023). I have also developed a novel animal model with amicroenvironment derived from human mesenchymal stem cell (MSC) that are able to maintain
HSC dormancy (Annu Rev Immunol., 2013; PNAS 2011; iScience 2019; Stem Cells Dev 2021).

Alloreactive T-cell targets tissue stem cells and impairs tissue homeostasis
in GVHD after allogeneic stem cell transplantation
Takanori Teshima(Hokkaido University)
Abstract:
Acute graft-versus-host disease (GVHD), a major complication after allogeneic hematopoietic
stem cell transplantation (alloSCT), is an alloreactive T-cell mediated inflammatory disease
involving the skin, liver, and gut. Our recent studies on the mechanisms of the target tissue injury
have uncovered that tissue stem cells in the GVHD target tissues are targets of GVHD, leading to
impaired tissue homeostasis and regeneration. Thus, GVHD can be recognized as a disorder oftissue regeneration and repair. Impairment of intestinal homeostasis disrupts intestinal microbial
ecology, which further accelerate GVHD. These novel insights suggests that immunosuppression
alone is not sufficient and novel concept of GVHD control should integrate bothimmunomodulation and tissue modulation. Novel strategies to increase capacity to recover when
immune insult is arrested could facilitate tissue repair and restoration of tissue homeostasis.

2-3 major papers:
1.
Ara T, Hashimoto D, Hayase E, Noizat C, Kikuchi R, Hasegawa Y, Matsuda K, Ono S, Matsuno
Y, Ebata K, Ogasawara R, Takahashi S, Ohigashi H, Yokoyama E, Matsuo K, Sugita J, Onozawa
M, Okumura R, Takeda K, Teshima T: Intestinal goblet cells protect against GVHD after
allogeneic stem cell transplantation via Lypd8. Sci Transl Med. 2020 Jul
1;12(550):eaaw0720.
2.
Peled JU, Gomes ALC, Devlin SM, Littmann ER, Taur Y, Sung AD, Weber D, Hashimoto D,
Slingerland AE, Slingerland JB, Maloy M, Clurman AG, Stein-Thoeringer CK, Markey KA,
Docampo MD, Burgos da Silva M, Khan N, Gessner A, Messina JA, Romero K, Lew MV, Bush
A, Bohannon L, Brereton DG, Fontana E, Amoretti LA, Wright RJ, Armijo GK, Shono Y,
Sanchez-Escamilla M, Castillo Flores N, Alarcon Tomas A, Lin RJ, Yáñez San Segundo L, Shah
GL, Cho C, Scordo M, Politikos I, Hayasaka K, Hasegawa Y, Gyurkocza B, Ponce DM, Barker
JN, Perales MA, Giralt SA, Jenq RR, Teshima T, Chao NJ, Holler E, Xavier JB, Pamer EG, vanden Brink MRM: Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell
Transplantation. N Engl J Med. 2020 Feb 27;382(9):822-834.
3.
Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, Musso M, Giebel S,
Uzay A, Langmuir P, Hollaender N, Gowda M, Stefanelli T, Lee SJ, Teshima T (equallycontributing senior author), Locatelli F: Ruxolitinib for Glucocorticoid-Refractory Chronic
Graft-versus-Host Disease. N Engl J Med. 2021 Jul 15;385(3):228-238.
Bio:
Dr. Teshima is a distinguished Professor at Hokkaido University. His clinical and research interests
are immune therapy such as allogeneic hematopoietic stem cell transplantation (HCT) and CAR-T
cell therapy. His major contributions include the discovery of the central role of cytokines in
GVHD leading to development of a novel GVHD treatment strategy using cytokine blockade andthe discovery of target tissue stem cell involvement with associated intestinal dysbiosis in GVHD
leading to a novel concept of GVHD control integrating both immunomodulation and tissue
modulation. Dr. Teshima takes the initiative of haploidentical HCT and CAR-T therapy as well as
numerous clinical trials of GVHD in Japan.

＊MEMO＊Welcome to Kumamoto!
Willkommen in Kumamoto!
Kumamoto University is located in Kumamoto city, which is at the center of the Kyushu island(Southwest Japan).Kumamoto is is not only a place blessed with natural resources like mountains,rivers, and oceans, but it is also quite rich in history and culture.

Kumamoto Castle is the most symbolic attraction in Kumamoto, which
has a history of more than 400 years. Its main feature is its stone walls,
known as Musha-gaeshi（武者返し）. These walls are warped toprevent enemy invasion. Unfortunately, in the earthquake of 2016,
Kumamoto Castle was severely damaged and is going through a 20years’ restoration.
The damage caused by the Kumamoto earthquake extends throughseveral areas of Kumamoto prefecture. The Aso area, which we will visiton this excursion, was one of the most damaged areas. However, we
would like you to see not only the great hurt that Kumamoto people has
experienced, but also their resilience and the way these people are
overcoming such adversities.
Aso is a place where you can feel the magnificence of nature
with your whole being. Despite being a place where you can feelthe danger of earthquakes and volcanic eruptions, the area is
blessed with rich groundwater and hot springs.
In fact, the groundwater which is nurturedby the Aso mountains, is one of the mostvaluable resources of Kumamoto City. Thisgroundwater provides for well-being of all
the 740,000 habitants of Kumamoto City.

Tokyo
Osaka
KumamotoWelcome to Kumamoto!
くまもとへようこそ！
The bountiful waters of Kumamoto also nurture
delicious food. All the famous foods in Kumamoto canbe summarised by the word ‘red’. Here is where we
produce the most amount of tomatoes andwatermelons in Japan. Basashi（馬刺し） is a must-try
food for visitors of Kumamoto, it is sashimi preparedwith horse meat instead of fish. Kumamoto is also
famous for its ‘Aka-Ushi’ (red cow) wagyu beef. In
Kumamoto, horses and cows live in the grasslands of
Aso and grow up drinking clean water and breathing
pure air, which make their meat delicious.
Kumamoto is proud of its “Sake（清酒/日本酒）”
and “Shochu（焼酎）”, made from a combinationof its nutritious water and locally-produced rice. In
fact, Kumamoto is the southernmost area where
sake is produced in its natural environment. In thepast, it was difficult to produce good sake due tothe weather, but people spent years doing
research to achieve the current amazing taste.
This achievement was only possible because of
Kumamoto yeast (No. 9 yeast). Interestingly,
Kumamoto yeast is still considered one of theconditions for making good sake, as yeast is an
important ingredient in the production of alcohol.
A yeast called Kumadai-Yeast was recently
In Hitoyoshi-Kuma area, the most southerly
discovered at Kumamoto University.
region of Kumamoto Prefecture, spirits alcohol
have been produced for more than 500 years.
The name Kuma-shochu is an alcoholic
beverage for which a specific regional name isused as a brand name, similar to Bordeaux forwine or Cognac for brandy. Kuma-Shochu has avariety of flavours depending on how it is madeand how it has aged. Two days is a short time,
but please enjoy Kumamoto!

Our Culture -- Kumadai-Hub!
Operated by Nanako Watanabe, Nazuki Doi and Hanami Sakai (IRCMS Admin)

Kumadai-Hub is an organization of “self-proclaimed”
young volunteers researchers at Kumamoto
University. It was founded in December 2019 and is
keep growing over the last few years. We use theterm “self-proclaimed” because the definition of“young” is ambiguous, so our members gather as“people with a fresh mind”. It started as a free small
gathering of researchers/research-enthusiasts fromdifferent areas, and has grown in size to about 110
members in a two years span.

Currently, Japanese universities’ policies are full of trendy
words

such

as

“internationalization,”“youngpeople’sdevelopment,”“jointresearch,”and“fusionresearch”. As much as these topics are important, nothingcompares to “our own mindset and actions”. In this sense,
we developed our community with the help of researchadministrator, emphasizing the fact that researchers need afixed space that they come and go when they need anddiscuss their ideas. Similar to what greeks would do inagoras, their public discussion spaces. We have regularquarterly meetings (once every three months) and also holddiverse social events. Recently some collaborations haveemerged through our activities. Despite being always on thelook for possibilities of “different fields’ collaboration” and“joint research development” that may emerge in themeetings, this is not our primary goal. We just want to makea fun place that let researchers discuss without barriers. Thisis the Kumadai-Hub’s main mission.

Kumadai-Hub is a group open not only to professional researchers, but also to students, technical staff,
administrative staff, and all others involved in university research. Despite Kumamoto University having
a large group of researchers spread through its five departments and three campuses. These
researchers don’t actually know each other very well. We had a poster exhibition in 2022 that provided
an opportunity for us to communicate with each other. The most interesting point was that technicaland administrative staff, who are usually on the management side, also made and exhibited posters to
introduce their own work. Researchers and students tried to avoid using “cryptic jargons” and focusedon having more friendly presentations. The most interesting part was that these rules were notsomething discussed on a gray room, but people came to this conclusion themselves. Studies andsciences are not exclusive and should not be restricted to a small group, so we need to be able to sharethem with everyone and explain them to anyone. We need more science communicators! This anotherof Kumadai-Hub’s missions.

Lastly, our community values face-to-face, but wealso value online connections. Since we are in
Japan, most members are more comfortable withJapanese, however we also communicate in English
and any other language is welcome. Our greatest

value is that we don’t have barriers based onwhether you are Japanese or non-Japanese, male orfemale, senior or young, your field of interest, or
your job title or position. Kumamoto University has
a place where we can discuss freely, flatly, andhappily.

About IRCMS

The International Research Center for Medical Sciences (IRCMS) was established in 2015 as the center of
excellence in Kumamoto University for world-class research in life sciences through the internationalizationof its research environment and the establishment of global collaborations.
The Center features an open lab layout with few walls and partitions between labs to facilitatecommunication among scientists. A meeting lounge and an open café on the 1st floor support active,
informal scientific exchange between researchers. English is the official language for all seminars and lab
meetings to promote international scientific discourse.
IRCMS is located in the Honjo-Kuhonji area
along with Kumamoto University’s School of
Medicine, the University Hospital, the Joint
Research Center for Human Retrovirus
Infection, the Institute of Resource
Development and Analysis (IRDA) and theInstitute of Molecular Embryology andGenetics (IMEG). Through cooperation withthese institutes, IRCMS will create a strong
collaborative network in the areas of Stem Cell
Research, Aging Research, Development
Research and Cancer Research.
At present, 12 principal investigators (PIs) and their lab members are conducting research at the Center.
IRCMS also aims to establish an international research collaboration network with visiting researchers who
hold positions in research institutes abroad. Non-Japanese nationals currently account for 40% of the people
working at the Center, excluding visiting researchers, and this number is expected to increase to 50% in the
future.
The ultimate goal of IRCMS is to become a successful and innovative role model for the internationalizationof academic research. IRCMS is now laying new framework that extends beyond the existing research
environment to reach this ultimate goal.

About IRCMS
IRCMS Global Partnerships

Open Lab / Core Facility
IRCMS has adopted an “Open Lab” System tostimulate scientific interaction among thescientists and cultivate inter-laboratory
collaboration across multiple disciplines.
Scientists share lab space and equipment. All of
the laboratories and office are visible throughthe window from the hallway.
To make research equipment sharing and time
management efficient, we have established an
online booking system and started technicalsupport for cutting-edge technology such as
single cell analysis. There is an open café spaceon the 1st floor to facilitate discussion andnetworking.

Open Lab

Core facility

Open space

Experiment in the lab

Internship
IRCMS has provided research internshipopportunities since 2015 for overseas students
who have a strong interest toward the advanced
medical research, aiming to raise the interest of
IRCMS research and recruit the next generation ofyoung researchers internationally.
We have invited more than 35 interns from 19
countries so far, and some of them came back to
IRCMS as Ph.D. course students or PostdocResearchers.

Conducting experimentResearch instruction

IRCMS Principal investigator
TAKIZAWA Hitoshi
Ph.D.
Professor (Director)
Research Field
Stem Cell Stress

ARIMA Yuichiro
M.D., Ph.D.
Associate Professor (Vice Director)
Research Field
Developmental Cardiology

SUDA Toshio
M.D., Ph.D.
Distinguished Professor
Research Field
Stem Cell Regulation
Double Appointment:
National University of Singapore

Guojun Sheng
Ph.D.
Professor
Research Field
Developmental Morphogenesis

SASHIDA Goro
M.D., Ph.D.
Professor
Research Field
Transcriptional Regulation in
Leukemogenesis

MIHARADA Kenichi
Ph.D.
Professor
Research Field
Proteostasis in Stem Cell

SADA Aiko
Ph.D.
Cross-appointment professor
Research Field
Skin Regeneration and Aging

BABA Masaya
M.D., Ph.D.
Associate Professor
Research Field
Cancer Metabolism

MIZUNO Hidenobu
Ph.D.
Associate Professor
Research Field
Multi-dimensional Imaging

UMEMOTO Terumasa
Ph.D.
Associate Professor
Research Field
Hematopoietic Stem Cell Engineering

KUROTAKI Daisuke
Ph.D.
Associate Professor
Research Field
Chromatin Organization in Immune Cell
Development

International Research Center for Medical Sciences,
Kumamoto University
2-2-1, Honjo, Chuo-ku, Kumamoto 860-0811 Japan
E-mail ircms@jimu.kumamoto-u.ac.jp