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Stem cell biology

Leukemia cell infiltration causes defective erythropoiesis partially through MIP-1α/CCL3

Leukemia volume 30, pages 1897–1908 (2016)Cite this article

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Abstract

Leukemia often results in severe anemia, which may significantly contribute to patient mortality and morbidity. However, the mechanisms underlying defective erythropoiesis in leukemia have not been fully elucidated. In this study, we demonstrated that insufficient erythropoiesis in an immunocompetent acute myeloid leukemia (AML) murine model was due to reduced proliferation of megakaryocyte erythroid progenitors and increased apoptosis of erythroblasts. Colony-forming cell assays indicated that the leukemic bone marrow (BM) plasma inhibited erythroid colony formation, whereas they had no inhibitory effect on other types of colonies. Cytokine array analysis demonstrated that the chemokine CCL3 was elevated in the plasma of AML mice and patients. CCL3 inhibited erythroid differentiation of hematopoietic stem cells, common myeloid progenitors and especially megakaryocytic-erythroid progenitors. Administration of the CCR1 antagonist partially recovered the yield of erythroid colonies in the presence of CCL3 or leukemic BM plasma. Mechanistically, we observed an increase of p38 phosphorylation and subsequent downregulation of GATA1 after CCL3 treatment. Furthermore, knockdown of CCL3 attenuated leukemic progression and alleviated anemia. Therefore, our results demonstrate that elevated CCL3 in the leukemic environment suppresses erythropoiesis via CCR1-p38 activation, suggesting a novel mechanism for the erythroid defects observed in leukemia.

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Acknowledgements

We thank Drs Xiuli An, Hideo Ema and Lihong Shi for their critical reading of our manuscript. We are also grateful to our lab members and collaborators for their assistance with the experiments and in the preparation of the manuscript. This work was supported by grants from the Ministry of Science and Technology of China (SQ2016ZY05002341, 2011CB964801, 2013CB966902 and 2015CB964902), the National Natural Science Foundation of China (81421002, 81090411, 81430004, 81300374, 81130074, 81400077, 81330015, and 81300375), and the General Financial Grant from the China Postdoctoral Science Foundation (2011M500263).

Author contributions

YW designed and performed all experiments, analyzed the data and wrote the manuscript. AG, HZ, LP and CH helped with all experiments and assisted with the manuscript. FD and SM helped with the mouse experiments and flow cytometry. YWZ, HZ and JX helped with the mouse experiments and western blottings. YCZ and XFZ provided the AML patient samples and helped with the experiments. WY analyzed the data and assisted with the manuscript. XBZ helped with the CRISPR/CAS9 experiments. SH designed all experiments, analyzed the data and wrote the manuscript. TC conceived the study, designed the experiments, interpreted the results, wrote the paper and oversaw the research project.

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Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China

    Y Wang, A Gao, H Zhao, P Lu, H Cheng, F Dong, Y Gong, S Ma, Y Zheng, H Zhang, Y Zhang, J Xu, X Zhu, W Yuan, X Zhang, S Hao & T Cheng

  2. Center for Stem Cell Medicine, Tianjin, China

    H Cheng, X Zhu, W Yuan, S Hao & T Cheng

  3. Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China

    X Zhu, W Yuan, X Zhang, S Hao & T Cheng

  4. Department of Medicine, Loma Linda University, Loma Linda, CA, USA

    X Zhang

  5. Collaborative Innovation Center for Cancer Medicine, Tianjin, China

    T Cheng

  6. Tianjin Key Laboratory of Blood Cell Therapy and Technology, Tianjin, China

    T Cheng

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Wang, Y., Gao, A., Zhao, H. et al. Leukemia cell infiltration causes defective erythropoiesis partially through MIP-1α/CCL3. Leukemia 30, 1897–1908 (2016). https://doi.org/10.1038/leu.2016.81

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