Cytoprotective autophagy maintains leukemia-initiating cells in murine myeloid leukemia

Yoshiki Sumitomo, Junji Koya, Kumi Nakazaki, Keisuke Kataoka, Takako Tsuruta-Kishino, Ken Morita, Tomohiko Sato, Mineo Kurokawa

研究成果: Article査読

32 被引用数 (Scopus)

抄録

Despite advances in the treatment of acute myeloid leukemia (AML), relapse and drug resistance frequently occur. Therefore, detailed mechanisms of refractoriness, including leukemia-initiating cell (LIC) biology, should be elucidated to treat AML. The selfdegradative property of cytosolic macromolecules is central to autophagy and can contribute to homeostasis and stress response. Recent reports suggest the importance of autophagy in hematopoietic stem cells and various tumors. Thus, this study investigated the functional role of autophagy in AML maintenance and drug resistance using tamoxifen-inducible conditional knockout mice of Atg5 or Atg7, which are essential genes for autophagy, combined with an mixed lineage leukemia-eleven nineteen leukemia-induced murine AML model. Inactivation of autophagy by deletion of Atg5 or Atg7 prolonged survival in leukemicmice and reduced functional LICs. Atg7-deficient LICs displayed enhancedmitochondrial activity and reactive oxygen species production together with increased cell death. In addition, Atg7 deletion markedly decreased peripheral blood leukemia cells, concurrent with increased apoptosis, suggesting a higher dependency on autophagy compared with bone marrowleukemia cells. Finally, cytarabine (AraC) treatment activated autophagy in LICs, and Atg7 deletion potentiated the therapeutic effects of AraC, which included decreased LICs and prolonged survival, suggesting that autophagy contributes to AraC resistance. Our results highlight the intratumoral heterogeneity related to autophagy in AML and the unique role of autophagy in leukemia development and drug resistance.

本文言語English
ページ(範囲)1614-1624
ページ数11
ジャーナルBlood
128
12
DOI
出版ステータスPublished - 2016
外部発表はい

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

フィンガープリント 「Cytoprotective autophagy maintains leukemia-initiating cells in murine myeloid leukemia」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

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