Dipeptide species regulate p38MAPK-Smad3 signalling to maintain chronic myelogenous leukaemia stem cells.
Understanding the specific survival of the rare chronic myelogenous leukaemia (CML) stem cell population could provide a target for therapeutics aimed at eradicating these cells. However, little is known about how survival signalling is regulated in CML stem cells. In this study, we survey global metabolic differences between murine normal haematopoietic stem cells (HSCs) and CML stem cells using metabolomics techniques. Strikingly, we show that CML stem cells accumulate significantly higher levels of certain dipeptide species than normal HSCs. Once internalized, these dipeptide species activate amino-acid signalling via a pathway involving p38MAPK and the stemness transcription factor Smad3, which promotes CML stem cell maintenance. Importantly, pharmacological inhibition of dipeptide uptake inhibits CML stem cell activity in vivo. Our results demonstrate that dipeptide species support CML stem cell maintenance by activating p38MAPK-Smad3 signalling in vivo, and thus point towards a potential therapeutic target for CML treatment.
Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.|Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Kazuhito
K
Naka
Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Yoshie
Y
Jomen
Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Kaori
K
Ishihara
CHA Cancer Institute and Department of Biomedical Science, CHA University, CHA Bio Complex, 335 Pangyo-ro, Bundang-ku, Seongnam, Kyunggi-do 463-400, Republic of Korea.
Junil
J
Kim
Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Takahiro
T
Ishimoto
Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.|CHA Cancer Institute and Department of Biomedical Science, CHA University, CHA Bio Complex, 335 Pangyo-ro, Bundang-ku, Seongnam, Kyunggi-do 463-400, Republic of Korea.
Eun-Jin
EJ
Bae
Metabolon, Inc., 617 Davis Drive Suite 400, Durham, North Carolina 27713, USA.
Robert P
RP
Mohney
Metabolon, Inc., 617 Davis Drive Suite 400, Durham, North Carolina 27713, USA.
Steven M
SM
Stirdivant
Division of Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Hiroko
H
Oshima
Division of Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Masanobu
M
Oshima
Department of Hematology, Seoul St Mary's Hospital, Cancer Research Institute, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea.
Dong-Wook
DW
Kim
Division of Stem Cell Therapy, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shiroganedai, Minato-ku, Tokyo 108-8639, Japan.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA.
Hiromitsu
H
Nakauchi
Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Yoshihiro
Y
Takihara
Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Yukio
Y
Kato
CHA Cancer Institute and Department of Biomedical Science, CHA University, CHA Bio Complex, 335 Pangyo-ro, Bundang-ku, Seongnam, Kyunggi-do 463-400, Republic of Korea.
Akira
A
Ooshima
CHA Cancer Institute and Department of Biomedical Science, CHA University, CHA Bio Complex, 335 Pangyo-ro, Bundang-ku, Seongnam, Kyunggi-do 463-400, Republic of Korea.
Seong-Jin
SJ
Kim
D000818:Animals; D018076:DNA, Complementary; D004151:Dipeptides / Q000145:classification* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D012190:Retroviridae; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D018076:DNA, Complementary; D004151:Dipeptides; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; D048051:p38 Mitogen-Activated Protein Kinases