TY - JOUR
T1 - ADAM8 Is an Antigen of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia Cells Identified by Patient-Derived Induced Pluripotent Stem Cells
AU - Miyauchi, Masashi
AU - Koya, Junji
AU - Arai, Shunya
AU - Yamazaki, Sho
AU - Honda, Akira
AU - Kataoka, Keisuke
AU - Yoshimi, Akihide
AU - Taoka, Kazuki
AU - Kumano, Keiki
AU - Kurokawa, Mineo
N1 - Funding Information:
We thank T. Kitamura for Plat-E and Plat-A packaging cells; H. Nakauchi for pGCDNsam-IRES-EGFP retroviral vector; T. Nagai for imatinib-resistant CML cell lines; K. Okita for pCXLE-hOCT3/4-shp53-F, pCXLE-hSK, pCXLE-hUL, and pCXWB-EBNA1; J.W. Bartsch for pCMV6-ADAM8-flag; Yoko Hokama and Keiko Tanaka for expert technical assistance; and Kyowa Hakko Kirin for recombinant human G-CSF. This work was supported in part by Advanced Research & Development Programs for Medical Innovation (AMED-CREST), the Japan Society for the Promotion of Science (JSPS) KAKENHI (no. 14J02953 and no. 16K19568 ), and a grant from the Foundation for Promotion of Cancer Research , Okinaka Memorial Institute for Medical Research and the Tokyo Biochemical Research Foundation . Since the current study started, M.K. has received an honorarium from Shionogi ; M.K. has received an honorarium from the Japan Science and Technology Agency ; M.K. has received research funding from Astellas , Bristol-Myers Squibb , Novartis , Pfizer , and Takeda ; S.A. has received research funding from Bristol-Myers Squibb and Novartis.
Funding Information:
We thank T. Kitamura for Plat-E and Plat-A packaging cells; H. Nakauchi for pGCDNsam-IRES-EGFP retroviral vector; T. Nagai for imatinib-resistant CML cell lines; K. Okita for pCXLE-hOCT3/4-shp53-F, pCXLE-hSK, pCXLE-hUL, and pCXWB-EBNA1; J.W. Bartsch for pCMV6-ADAM8-flag; Yoko Hokama and Keiko Tanaka for expert technical assistance; and Kyowa Hakko Kirin for recombinant human G-CSF. This work was supported in part by Advanced Research & Development Programs for Medical Innovation (AMED-CREST), the Japan Society for the Promotion of Science (JSPS) KAKENHI (no. 14J02953 and no. 16K19568), and a grant from the Foundation for Promotion of Cancer Research, Okinaka Memorial Institute for Medical Research and the Tokyo Biochemical Research Foundation. Since the current study started, M.K. has received an honorarium from Shionogi; M.K. has received an honorarium from the Japan Science and Technology Agency; M.K. has received research funding from Astellas, Bristol-Myers Squibb, Novartis, Pfizer, and Takeda; S.A. has received research funding from Bristol-Myers Squibb and Novartis.
Publisher Copyright:
© 2018 The Authors
PY - 2018/3/13
Y1 - 2018/3/13
N2 - Properties of cancer stem cells involved in drug resistance and relapse have significant effects on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myeloid leukemia (CML), TKIs have not fully cured CML due to TKI-resistant CML stem cells. Moreover, relapse after discontinuation of TKIs has not been predicted in CML patients with the best TKI response. In our study, a model of CML stem cells derived from CML induced pluripotent stem cells identified ADAM8 as an antigen of TKI-resistant CML cells. The inhibition of expression or metalloproteinase activity of ADAM8 restored TKI sensitivity in primary samples. In addition, residual CML cells in patients with optimal TKI response were concentrated in the ADAM8+ population. Our study demonstrates that ADAM8 is a marker of residual CML cells even in patients with optimal TKI response and would be a predictor of relapse and a therapeutic target of TKI-resistant CML cells. The paucity and heterogeneity of CML stem cells are obstacles for analyses. In our study, a model of CML stem cells derived from CML-iPSCs identified ADAM8 as an antigen of TKI-resistant cells. In CML patients, ADAM8+ cells showed TKI resistance and residual CML cells after TKIs-treatment were concentrated in ADAM8+ population, suggesting that ADAM8 is a marker of TKI-resistant CML cells.
AB - Properties of cancer stem cells involved in drug resistance and relapse have significant effects on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myeloid leukemia (CML), TKIs have not fully cured CML due to TKI-resistant CML stem cells. Moreover, relapse after discontinuation of TKIs has not been predicted in CML patients with the best TKI response. In our study, a model of CML stem cells derived from CML induced pluripotent stem cells identified ADAM8 as an antigen of TKI-resistant CML cells. The inhibition of expression or metalloproteinase activity of ADAM8 restored TKI sensitivity in primary samples. In addition, residual CML cells in patients with optimal TKI response were concentrated in the ADAM8+ population. Our study demonstrates that ADAM8 is a marker of residual CML cells even in patients with optimal TKI response and would be a predictor of relapse and a therapeutic target of TKI-resistant CML cells. The paucity and heterogeneity of CML stem cells are obstacles for analyses. In our study, a model of CML stem cells derived from CML-iPSCs identified ADAM8 as an antigen of TKI-resistant cells. In CML patients, ADAM8+ cells showed TKI resistance and residual CML cells after TKIs-treatment were concentrated in ADAM8+ population, suggesting that ADAM8 is a marker of TKI-resistant CML cells.
KW - TKI-resistant CML stem cells
KW - chronic myeloid leukemia
KW - disease specific iPSCs
UR - http://www.scopus.com/inward/record.url?scp=85041688387&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041688387&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2018.01.015
DO - 10.1016/j.stemcr.2018.01.015
M3 - Article
C2 - 29429960
AN - SCOPUS:85041688387
SN - 2213-6711
VL - 10
SP - 1115
EP - 1130
JO - Stem cell reports
JF - Stem cell reports
IS - 3
ER -
