ADAM8 Is an Antigen of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia Cells Identified by Patient-Derived Induced Pluripotent Stem Cells

Masashi Miyauchi, Junji Koya, Shunya Arai, Sho Yamazaki, Akira Honda, Keisuke Kataoka, Akihide Yoshimi, Kazuki Taoka, Keiki Kumano, Mineo Kurokawa

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1115-1130
Number of pages16
JournalStem cell reports
Volume10
Issue number3
DOIs
Publication statusPublished - 2018 Mar 13

Keywords

  • TKI-resistant CML stem cells
  • chronic myeloid leukemia
  • disease specific iPSCs

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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