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Novel regulators in hematopoietic stem cells can be revealed by a functional approach under leukemic condition

Leukemia volume 30, pages 2074–2077 (2016)Cite this article

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Among the candidate genes we described in our previous study,8 Maff and Hey1 were markedly upregulated in normal Lineage−c-Kit+Sca-1+ (LKS+) cells in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia models (Figure 1b; Supplementary Figure S1A). This result was confirmed using qRT-PCR analysis (Figure 1c). We next performed studies to test whether Maff and Hey1 were also highly expressed in LKS+CD34− LT-HSCs from leukemic bone marrow (BM). The BioMark 48.48 Dynamic Array (Biomark, Fluidigm Corporation, South San Francisco, CA, USA) qPCR system was used to quantify the gene expression. LKS+CD34− LT-HSCs (and LKS+CD34+ ST-HSCs) from leukemic BM expressed these two genes at more than threefold (and twofold) the level observed in LT-HSCs (and ST-HSCs) from control BM (Figure 1d). A previous study demonstrated that Maff and Hey1 were significantly overexpressed in purified HSCs relative to other cell type (Supplementary Figure S1B).6 To confirm this result, hematopoietic stem, progenitor and mature cell populations were isolated from the BM of B6-Ly5.2 mice, and the relative expression levels of Maff and Hey1 were measured by qRT-PCR. Consistent with the previous study, Maff and Hey1 were specifically highly expressed in LT-HSCs (Figure 1e). This result suggests a potential role for these two genes in HSCs, which prompted us to further investigate their functions in hematopoiesis, especially in HSCs.

To determine the function of Maff and Hey1 in hematopoiesis, we first used zebrafish to characterize their function during development. We performed knockdown experiments in zebrafish using antisense morpholinos (MOs) that targets the region surrounding the translation start codon of the Maff and Hey1 transcripts. The effectiveness of the translation inhibition of the MOs was tested by examining the in vivo green fluorescent fusion protein. The Maff and Hey1 knockdown embryos (morphants) exhibited an overall normal morphology, with no visible alterations in the patterning of the central nervous system. However, using O-dianisidine hemoglobin staining, we observed significantly decreased mature erythroid cells; there were only a few differentiated red blood cells within the sinus venosus in the Maff and Hey1 morphants (Supplementary Figure S2A).

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Acknowledgements

We are 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 (2016ZY05002341, 2011CB964801, 2012CB966601, 2013CB945300, 2013CB966902 and 2015CB964400) and from the National Nature Science Foundation of China (81421002, 81090411, 81430004, 81330015, 81130074, 81400077, 81300375 and 81500085), and from SKLEH-Pilot Research (ZK12-05, ZK13-03).

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Authors and Affiliations

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

    H Cheng, S Ma, W Yuan & T Cheng

  2. Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China

    H Cheng, W Yuan & T Cheng

  3. Qilu Hospital, Shandong University, Jinan, China

    Y Liu

  4. Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Q Jia & H Jia

  5. Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China

    W Yuan & T Cheng

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

    T Cheng

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Correspondence to T Cheng.

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Cheng, H., Liu, Y., Jia, Q. et al. Novel regulators in hematopoietic stem cells can be revealed by a functional approach under leukemic condition. Leukemia 30, 2074–2077 (2016). https://doi.org/10.1038/leu.2016.118

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