「様式３－B」

課題番号（Project number）31

Roles of KEAP1-NRF2 system
in long-term hematopoietic stem cells［１］組織（Research group）
代表者（Principal Investigator (PI)）：
Paul-Henri Romeo（Inserm, France）
対応者（Host researcher at IDAC）：
Hozumi Motohashi（IDAC Tohoku University）
研 究 費 (Expenditure report of researchfunds)：
Travel cost, 370,074 YEN
Consumables, 23,969 YEN，
Charge for IDAC Research Core, 5,957 YEN,［２］研究経過（Research setup）
KEAP1-NRF2 system plays a central role in thedefense mechanisms against oxidative andxenobiotic stresses. We recently found that
long-term hematopoietic stem cells (LT-HSCs) arevery sensitive to low dose irradiation, andclarified that generation of oxidative stress is themajor cause of the loss of LT-HSCs after thelow-dose irradiation rather than provoking DNA
damage. We also found that, in LT-HSCs, NRF2
accumulation is triggered after the low-dose
irradiation and that NRF2 target genes areinduced, suggesting that NRF2 contributes to theprotection of the LT-HSCs from the low-dose
irradiation-induced oxidative stress. Based onthese results, we aimed at testing whether
constitutive enhancement of NRF2 activity in
LT-HSCs is beneficial for maintaining thestemness and delay the senescent phenotype of
LT-HSCs. Our goal is to establish a new
therapeutic target for the prevention of tissue
damage, particularly loss of tissue stem cells,
from low-dose irradiation.
To achieve this goal, I visited Prof.
Motohashi’s lab last May and had intensive
discussion with her lab members.

［３］成果（Research outcomes）（３－１）研究成果（Results）
We clarified that LT-HSCs are hypersensitive to
low-dose irradiation and that the hypersensitivity
is not associated with DNA damage but withincrease in the reactive oxygen species (ROS)
levels. The low dose irradiation induced NRF2,
which is beneficial for the protection of LT-HSCs.
On the side of Prof. Motohashi’s group,
they examined LT-HSCs in which NRF2 isgenetically activated by disruption of Keap1.
They found that continuous activation of NRF2
by Keap1 disruption expands progenitor
population and promotes cell cycle entry ofLT-HSCs in steady state hematopoiesis, andimpairs bone marrow reconstitution ability ofLT-HSCs in hematopoietic regeneration.
These results suggest that appropriate
control of NRF2 by KEAP1 is essential for
protecting LT-HSCs from oxidative damages andsaving LT-HSCs by avoiding unnecessary
activation and differentiation.
（３－２）波及効果と発展性など（Futureperspectives）
Outcomes of this joint research will establish a
new concept regarding the environmental
response of LT-HSCs and their aging phenotypes
that develop after repetitive exposure to theenvironmental stresses.

［４］成果資料（List of Papers）（１）Shohei Murakami, Takuma Suzuki,Paul-Henri Romeo, Masayuki Yamamoto,
Hozumi Motohashi. NRF2 activation impairs
quiescence and bone marrow reconstitution
capacity of hematopoietic stem cells. Submitted.
（２）Shohei Murakami, Hozumi Motohashi.
Recent advances in elucidating KEAP1-NRF2
functions in hematopoietic/immune cells andleukemic cells. Rinsho Ketsuoki 57, 1860-1868,2016.
（３）Shohei Murakami, Masayuki Yamamoto,Hozumi Motohashi. KEAP1-NRF2 function inhematopoietic stem cells. The 89th JBS annualmeeting. Sendai International ConferenceCenter, Snedai, Sep. 25-27, 2016.