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Stem cell biology

The immune receptor Trem1 cooperates with diminished DNA damage response to induce preleukemic stem cell expansion

Leukemia volume 31, pages 423–433 (2017)Cite this article

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Abstract

Fanconi anemia (FA) is an inherited bone marrow failure syndrome with extremely high risk of leukemic transformation. Here we investigate the relationship between DNA damage response (DDR) and leukemogenesis using the Fanca knockout mouse model. We found that chronic exposure of the Fanca−/− hematopoietic stem cells to DNA crosslinking agent mitomycin C in vivo leads to diminished DDR, and the emergence/expansion of pre-leukemia stem cells (pre-LSCs). Surprisingly, although genetic correction of Fanca deficiency in the pre-LSCs restores DDR and reduces genomic instability, but fails to prevent pre-LSC expansion or delay leukemia development in irradiated recipients. Furthermore, we identified transcription program underlying dysregulated DDR and cell migration, myeloid proliferation, and immune response in the Fanca−/− pre-LSCs. Forced expression of the downregulated DNA repair genes, Rad51c or Trp53i13, in the Fanca−/− pre-LSCs partially rescues DDR but has no effect on leukemia, whereas shRNA knockdown of the upregulated immune receptor genes Trem1 or Pilrb improves leukemia-related survival, but not DDR or genomic instability. Furthermore, Trem1 cooperates with diminished DDR in vivo to promote Fanca−/− pre-LSC expansion and leukemia development. Our study implicates diminishing DDR as a root cause of FA leukemogenesis, which subsequently collaborates with other signaling pathways for leukemogenic transformation.

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Acknowledgements

We thank Dr Madeleine Carreau (Laval University) for Fanca+/− mice, Dr Manuel Buchwald (University of Toronto) for Fancc+/− mice, Dr Lenhand Rudolph (Institute of Molecular Medicine and Max-Planck-Research, Germany) for SF-LV-shRNA-EGFP vector, Dr Punam Malik (Cincinnati Children’s Hospital Medical Center) for the pRRL-SIN-cPPTMNDU3-MCS-IVW (TMND-IRES-Venus) vector, the Viral Vector Core of Cincinnati Children’s Research Foundation (Cincinnati Children’s Hospital Medical Center) for the preparation of viruses, and the Comprehensive Mouse and Cancer Core of the Cincinnati Children’s Research Foundation (Cincinnati Children’s Hospital Medical Center) for BM transplantation service. This investigation was supported by National Institutes of Health grants R01 HL076712, R01 CA157537 and T32 HL091805. QP is supported by a Leukemia and Lymphoma Scholar award. WD is supported by National Natural Science Fundation of China 81470288.

Author contributions

WD designed the research, performed the research, analyzed the data and wrote the paper; SA performed the research and analyzed the data; AFW performed the research; QP designed the research and wrote the paper.

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Authors and Affiliations

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

    W Du, S Amarachintha, A Wilson & Q Pang

  2. Divisions of Radiation Health, Department of Pharmaceutical Science, College of Pharmacy, UAMS, Little Rock, AR, USA

    W Du

  3. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Q Pang

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Correspondence to W Du or Q Pang.

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Du, W., Amarachintha, S., Wilson, A. et al. The immune receptor Trem1 cooperates with diminished DNA damage response to induce preleukemic stem cell expansion. Leukemia 31, 423–433 (2017). https://doi.org/10.1038/leu.2016.242

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