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Epidemiology

The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of Hoxa7 and Hoxa9

Leukemia volume 31, pages 712–719 (2017)Cite this article

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Abstract

Acute myelogenous leukemia (AML) is a high-risk hematopoietic malignancy caused by a variety of mutations, including genes encoding the cohesin complex. Recent studies have demonstrated that reduction in cohesin complex levels leads to enhanced self-renewal in hematopoietic stem and progenitors (HSPCs). We sought to delineate the molecular mechanisms by which cohesin mutations promote enhanced HSPC self-renewal as this represents a critical initial step during leukemic transformation. We verified that RNAi against the cohesin subunit Rad21 causes enhanced self-renewal of HSPCs in vitro through derepression of polycomb repressive complex 2 (PRC2) target genes, including Hoxa7 and Hoxa9. Importantly, knockdown of either Hoxa7 or Hoxa9 suppressed self-renewal, implying that both are critical downstream effectors of reduced cohesin levels. We further demonstrate that the cohesin and PRC2 complexes interact and are bound in close proximity to Hoxa7 and Hoxa9. Rad21 depletion resulted in decreased levels of H3K27me3 at the Hoxa7 and Hoxa9 promoters, consistent with Rad21 being critical to proper gene silencing by recruiting the PRC2 complex. Our data demonstrates that the cohesin complex regulates PRC2 targeting to silence Hoxa7 and Hoxa9 and negatively regulate self-renewal. Our studies identify a novel epigenetic mechanism underlying leukemogenesis in AML patients with cohesin mutations.

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Acknowledgements

We thank Hope Campbell and Benedetta Bonacci for their assistance with flow cytometry. S Rao is supported by grants from the Midwest Athletes Against Childhood Cancer (MACC Fund), Hyundai Hope on Wheels and an American Society of Hematology Bridge Grant. Additional research support to S Rao was provided by charitable gifts from Hartland Blood Centers, Ms Nanette Gardetto and Mr Doug Ziegler.

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  1. J B Fisher and J Peterson: These authors contributed equally to this work.

Authors and Affiliations

  1. Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA

    J B Fisher, J Peterson, M Reimer, C Stelloh, K Pulakanti, S Malarkannan & S Rao

  2. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA

    M Reimer & S Rao

  3. Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA

    Z J Gerbec, A M Abel & S Malarkannan

  4. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    J M Strouse, S Malarkannan & S Rao

  5. Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    C Strouse & S Malarkannan

  6. Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA

    M McNulty & J D Crispino

  7. Sanford Research Center and University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA

    S Milanovich

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Fisher, J., Peterson, J., Reimer, M. et al. The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of Hoxa7 and Hoxa9. Leukemia 31, 712–719 (2017). https://doi.org/10.1038/leu.2016.240

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