SALL4 is a key transcription regulator in normal human hematopoiesis

Authors

  • Chong Gao,

    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
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    • These authors contributed equally to the work.

  • Nikki R. Kong,

    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
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    • These authors contributed equally to the work.

  • Ailing Li,

    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
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  • Hiro Tatetu,

    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
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  • Shikiko Ueno,

    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
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  • Youyang Yang,

    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
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  • Jie He,

    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
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  • Jianchang Yang,

    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
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  • Yupo Ma,

    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
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  • Grace S. Kao,

    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
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  • Daniel G. Tenen,

    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
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  • Li Chai

    Corresponding author
    1. From the Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, and the Joint Program in Transfusion Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; the Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, Nevada; the Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; and the Harvard Stem Cell Institute, Center for Life Science, Boston, Massachusetts.
      L. Chai, Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB652, Boston, MA 02115; e-mail: lchai@partners.org.
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L. Chai, Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB652, Boston, MA 02115; e-mail: lchai@partners.org.

Abstract

BACKGROUND: Stem cell factor SALL4 is a zinc finger transcription factor. It plays vital roles in the maintenance of embryonic stem cell properties, functions as an oncogene in leukemia, and has been recently proposed to use for cord blood expansion. The mechanism(s) by which SALL4 functions in normal human hematopoiesis, including identification of its target genes, still need to be explored.

STUDY DESIGN AND METHODS: Chromatin immunoprecipitation followed by microarray hybridization (ChIP-chip) was used for mapping SALL4 global gene targets in normal primary CD34+ cells. The results were then correlated with SALL4 functional studies in the CD34+ cells.

RESULTS: More than 1000 potential SALL4 downstream target genes have been identified, and validation of binding by ChIP-quantitative polymerase chain reaction was performed for 5% of potential targets. These include genes that are involving in hematopoietic differentiation and self-renewal, such as HOXA9, RUNX1, CD34, and PTEN. Down regulation of SALL4 expression using small-hairpin RNA in these cells led to decreased in vitro myeloid colony–forming abilities and impaired in vivo engraftment. Furthermore, HOXA9 was identified to be a major SALL4 target in normal human hematopoiesis and the loss of either SALL4 or HOXA9 expression in CD34+ cells shared a similar phenotype.

CONCLUSION: Taken together, SALL4 is a key regulator in normal human hematopoiesis and the mechanism of its function is at least in part through the HOXA9. Future study will determine whether modulating the SALL4/HOXA9 pathway can be used in cellular therapy such as cord blood expansion and/or myeloid engraftment.

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