Cytoprotective autophagy maintains leukemia-initiating cells in murine myeloid leukemia

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

doi:10.1182/blood-2015-12-684696

Cited by 68 publications

(68 citation statements)

References 52 publications

(56 reference statements)

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“…Figure 1J,K). These data are consistent with recent publications 7,8,12 , and demonstrate that Atg7 is required for the efficient generation of AML in vivo, however we note that AML penetrance was 100% even in the complete absence of autophagic flux, suggesting that full leukemic transformation may be sufficient to overcome this requirement for autophagy. Moreover, although LysM expression is active in GMPs in normal hematopoiesis, LysMCre does not efficiently excise Atg7 within LSC populations and should not be used to test gene function in AML LSC models.…”

supporting

confidence: 93%

“…Within the hematopoietic system, autophagy has diverse roles and is required for hematopoietic stem cell (HSC) function 2 , differentiation into erythroid 3 or T-lymphoid lineages 4,5 and response to extracellular cytokine signaling 6 . In blood cancers such as acute myeloid leukaemia (AML), modulating autophagy has been proposed as a novel therapy to treat AML 1,7,8 . Leukemia stem cell (LSC) populations initiate and maintain leukemia in vivo.…”

mentioning

confidence: 99%

“…In particular, some important technical differences between studies may potentially explain the apparent discrepancies. Conditional Atg7 deletion using tamoxifen to induce Cre expression (using the Rosa26-CreERT and compared to saline controls) slowed the progression of MLL-ENL AML and also had modest effects on secondary transplantation 8 . This study used MLL-ENL, an oncogene that is most frequently associated with human acute lymphoblastic leukemia 14 .…”

mentioning

confidence: 99%

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Acute myeloid leukemia stem cell function is preserved in the absence of autophagy

et al. 2017

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confidence: 93%

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confidence: 99%

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Acute myeloid leukemia stem cell function is preserved in the absence of autophagy

et al. 2017

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“…12 Mounts of studies indicated that autophagy played a cytoprotective role in pathogenesis process and antitumor therapy. 13 Notably, more and more evidences indicated that reactive oxygen species (ROS) were also strongly involved in the response to cancer therapeutics. 14 Thus, stimulation of autophagy by rhArg through depleting arginine and mitochondrial-derived ROS production have been highlighted in the treatment with rhArg for NSCLC.…”

mentioning

confidence: 99%

A novel and promising therapeutic approach for NSCLC: recombinant human arginase alone or combined with autophagy inhibitor

Shen

Zhang

et al. 2017

Cell Death Dis

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Recombinant human arginase (rhArg), an enzyme capable of depleting arginine, has been shown to be an effective therapeutic approach for various cancers. Non-small-cell lung cancer (NSCLC), a histological subtype of pulmonary carcinoma, has a high rate of morbidity and mortality in the world. Thus, the need for novel and more effective treatment is urgent. In this study, it is the first time to report that rhArg could induce significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells. Subsequently, our research revealed that rhArg dramatically stimulated autophagic response in NSCLC cells, which was proved by the formation and accumulation of autophagosomes and the conversion of microtubule-associated protein light chain 3 (LC3) from LC3-I to LC3-II. Furthermore, blocking autophagy by chloroquine or LY294002 remarkably enhanced rhArg-induced cytotoxicity and caspase-dependent apoptosis, suggesting that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells. Further experiments showed that two signaling pathways including the Akt/mTOR and extracellular signal-regulated kinase pathway, and mitochondrial-derived reactive oxygen species (ROS) production were involved in rhArg-induced autophagy and apoptosis. Meanwhile, N-acetyl-L-cysteine, a common antioxidant, was employed to scavenge ROS, and we detected that it could significantly block rhArg-induced autophagy and cytotoxicity, indicating that ROS played a vital role in arginine degradation therapy. Besides, xenograft experiment showed that combination with autophagy inhibitor potentiated the anti-tumor efficacy of rhArg in vivo. Therefore, these results provided a novel prospect and viewpoint that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells, and treatment with rhArg alone or combined with autophagy inhibitor could be a novel and promising therapeutic approach for NSCLC in vivo and in vitro.

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“…Moreover, mTORC-S6K1 pathway has been shown to be a critical regulator of integral cellular processes like metabolism and autophagy. Recent findings show that metabolism (72, 73) and autophagy (74-76) are critical regulators of LSC maintenance. Additionally, mTORC1-S6K1 pathway could also reprogram metabolic pathways in malignant cells to help the cells escape glycolysis dependency and become resistance to inhibition of cellular glycolysis (77).…”

Section: Future Directionsmentioning

confidence: 99%

Role of mTORC1–S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leukemia

Ghosh

Kapur

2017

Experimental Hematology

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Dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1)-p70 ribosomal protein kinase 1 (S6K1) signaling pathway occurs frequently in acute myeloid leukemia (AML) patients. This pathway also plays a critical role in maintaining normal cellular processes. Given the importance of leukemia stem cells (LSC) in the development of minimal residual disease (MRD), it is critical to use therapeutic interventions that target LSC population to prevent disease relapse. mTORC1-S6K1 pathway has been identified as an important regulator of hematopoietic stem cell (HSC) and LSC functions. Both HSC and LSC functions require regulation of key cellular processes including proliferation, metabolism and autophagy, which are regulated by mTORC1 pathway. Despite mTORC1-S6K1 pathway being a critical regulator of AML initiation and progression, inhibitors of this pathway alone have yielded mixed results in clinical studies. Recent studies have identified strategies to develop new mTORC1-S6K1 inhibitors like RapaLink-1, which could circumvent the drug resistance observed in AML cells as well as in LSC. In this article, we review recent advances made in identifying the role of different components of this pathway in the regulation of HSC and LSC along with possible therapeutic approaches.

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Cytoprotective autophagy maintains leukemia-initiating cells in murine myeloid leukemia

Cited by 68 publications

References 52 publications

Acute myeloid leukemia stem cell function is preserved in the absence of autophagy

Acute myeloid leukemia stem cell function is preserved in the absence of autophagy

A novel and promising therapeutic approach for NSCLC: recombinant human arginase alone or combined with autophagy inhibitor

Role of mTORC1–S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leukemia

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