Original Article | Published:

Stem cell biology

Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow

Leukemia volume 30, pages 154162 (2016) | Download Citation

Abstract

Degeneration of normal hematopoietic cells is a shared feature of malignant diseases in the hematopoietic system. Previous studies have shown the exhaustion of hematopoietic progenitor cells (HPCs) in leukemic marrow, whereas hematopoietic stem cells (HSCs) remain functional upon relocation to non-leukemic marrow. However, the underlying cellular mechanisms, especially the specific niche components that are responsible for the degeneration of HPCs, are unknown. In this study, we focused on murine bone mesenchymal stem cells (MSCs) and their supporting function for normal hematopoietic cells in Notch1-induced acute T-cell lymphocytic leukemia (T-ALL) mice. We demonstrate that the proliferative capability and differentiation potential of T-ALL MSCs were impaired due to accelerated cellular senescence. RNA-seq analysis revealed significant transcriptional alterations in leukemic MSCs. After co-cultured with the MSCs from T-ALL mice, a specific inhibitory effect on HPCs was defined, whereas in vivo repopulating potential of normal HSCs was not compromised. Furthermore, osteoprotegerin was identified as a cytokine to improve the function of T-ALL MSCs and to enhance normal HPC output via the p38/ERK pathway. Therefore, this study reveals a novel cellular mechanism underlying the inhibition of HPC generation in T-ALL. Leukemic MSCs may serve as a cellular target for improving normal hematopoietic regeneration therapeutically.

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Acknowledgements

We would like to thank Drs David T Scadden, Paul S Frenette and Tsvee Lapidot for their valuable input on this work. We are also grateful to our lab members and collaborators for assisting with the experiments and with the manuscript preparation. This study was supported by grants from the Ministry of Science and Technology of China (2011CB964801, 2012CB966601 and 2013CB966902) and from the National Natural Science Foundation of China (81090411, 81421002, 81330015, 81300374, 81300375, and 81430004).

Author contributions

ML and YP designed and performed the experiments, analyzed data and wrote the paper. SM and SH performed Fluidigm microfluidic chips for qRT-PCR. YZ, CH and XG helped isolate PαS MSCs and LSK cells. WY and FY helped analyze data and assisted with the manuscripts. TC conceived the study, designed the experiments, interpreted the results, wrote the paper and oversaw the research project.

Author information

Author notes

    • M Lim
    •  & Y Pang

    These authors contributed equally to this study.

Affiliations

  1. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical Colleage, Tianjin, China

    • M Lim
    • , Y Pang
    • , S Ma
    • , S Hao
    • , H Shi
    • , Y Zheng
    • , C Hua
    • , X Gu
    • , W Yuan
    •  & T Cheng
  2. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    • F Yang
  3. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA

    • F Yang
  4. Center for Stem Cell Medicine and Department of Stem Cell & Regenerative Medicine, Chinese Academy of Medical Sciences and Peking Union Medical Colleage, Tianjin, China

    • T Cheng
  5. Collaborative Innovation Center for Cancer Medicine, Tianjin, China

    • T Cheng

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to T Cheng.

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DOI

https://doi.org/10.1038/leu.2015.210

Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)

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