General AML

Cytoprotective autophagy maintains leukemia-initiating cells in murine myeloid leukemia

Autophagy is an important self-degradative process involved in responding to stress and homeostasis. This process has implications in the development of hematological malignancies such as Acute Myeloid Leukemia (AML). Consequently, further understanding of the control of autophagy could lead to improved clinical outcomes for patients with AML.

Sumitomo, et al., of the Graduate School of Medicine, Japan, investigated the role of autophagy in AML maintenance and drug resistance in knockout mice of Atg5 or Atg7 with mixed linkage leukemia. The key findings of their study identified new potential therapeutic methods of optimizing AraC chemotherapy. Furthermore, by elucidating the functional role of autophagy in AML, the authors have provided further insights into the progression of the disease. Their results were published in Blood in July 2016. Please find the abstract of the study below.

Abstract

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 self-degradative 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 leukemic mice and reduced functional LICs. Atg7-deficient LICs displayed enhanced mitochondrial 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 marrow leukemia 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.

References
  1. Sumitomo Y. et al. Cytoprotective autophagy maintains leukemia-initiating cells in murine myeloid leukemia. Blood. 2016; 128:1614–1624. DOI:10.1182/blood-2015-12-684696.
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