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mTOR kinase inhibitor sensitizes T-cell lymphoblastic leukemia for chemotherapy-induced DNA damage via suppressing FANCD2 expression

Leukemia volume 28, pages 203–206 (2014)Cite this article

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Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and has a critical role in mammalian cell growth, survival and metabolism. mTOR is present in two cellular complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).1, 2 Dysregulation of the mTOR pathway has been related to tumorigenesis, poor prognosis and/or chemotherapy resistance in several malignancies including leukemia.3, 4 Inhibition of mTORC1 by rapamycin and its analogs has been explored to treat tumors from various cellular origins. However, the effectiveness of patient response is limited and not all patients respond.5, 6, 7, 8 Second generation of mTOR inhibitors have recently been developed to target mTOR kinase activity and to suppress both mTORC1 and mTORC2.9, 10

Fanconi anemia (FA) is a genomic instability syndrome that is defective for a DNA damage response pathway resulting in cellular hypersensitivity to DNA-damaging agents.11 Mutation or silencing of genes controlling the FA pathway has been linked to reduced genomic stability and is associated with increased drug sensitivity.12 Therefore, inhibition of the FA pathway combined with DNA-damaging anticancer drugs may represent a promising strategy for cancer therapy.

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Acknowledgements

We thank Dr Alan D'Andrea (Harvard Medical School) for the pMMP-Puro and pMMP-FANCD2 retroviral vectors, Dr Xiaoli Li and Jonathan Schick for technical assistance, the Vector Core of the Cincinnati Children's Research Foundation (Cincinnati Children’s Hospital Medical Center) for the preparation of retroviruses, the Comprehensive Mouse and Cancer Core of the Cincinnati Children's Research Foundation (Cincinnati Children’s Hospital Medical Center) for bone marrow transplantation service and Leesa Sampson for data analysis. This investigation was supported by NIH grants R01 HL076712, R01 CA157537, P30 DK090971 and T32 HL091805. QP is supported by a Leukemia and Lymphoma Scholar award. WD is supported by a NIH T32 training grant.

Author contributions

FG designed and performed research, contributed vital new reagents or analytical tools, analyzed data, and wrote the paper; JL designed and performed research, analyzed data and wrote the paper; SZ performed research and analyzed data; WD performed research and analyzed data; SA performed research and analyzed data; JS performed research and analyzed data; JP performed research and analyzed data; HLG designed research and contributed vital new reagents; YZ designed research, contributed vital new reagents, analyzed data and wrote the paper. QP designed research, contributed vital new reagents, analyzed data and wrote the paper.

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  1. F Guo and J Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    F Guo, J Li, S Zhang, W Du, S Amarachintha, J Sipple, Y Zheng & Q Pang

  2. Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    J Phelan & H L Grimes

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  1. F Guo
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Correspondence to Y Zheng or Q Pang.

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Guo, F., Li, J., Zhang, S. et al. mTOR kinase inhibitor sensitizes T-cell lymphoblastic leukemia for chemotherapy-induced DNA damage via suppressing FANCD2 expression. Leukemia 28, 203–206 (2014). https://doi.org/10.1038/leu.2013.215

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