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MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment

Author

Listed:
  • Vincenzo Calvanese

    (University of California Los Angeles
    University of California Los Angeles)

  • Andrew T. Nguyen

    (University of California Los Angeles)

  • Timothy J. Bolan

    (University of California Los Angeles)

  • Anastasia Vavilina

    (University of California Los Angeles)

  • Trent Su

    (University of California Los Angeles)

  • Lydia K. Lee

    (University of California Los Angeles)

  • Yanling Wang

    (University of California Los Angeles)

  • Fides D. Lay

    (University of California Los Angeles)

  • Mattias Magnusson

    (University of California Los Angeles
    University of California Los Angeles)

  • Gay M. Crooks

    (University of California Los Angeles
    University of California Los Angeles
    University of California Los Angeles)

  • Siavash K. Kurdistani

    (University of California Los Angeles
    University of California Los Angeles
    University of California Los Angeles
    University of California Los Angeles)

  • Hanna K. A. Mikkola

    (University of California Los Angeles
    University of California Los Angeles
    University of California Los Angeles
    University of California Los Angeles)

Abstract

Limited knowledge of the mechanisms that govern the self-renewal of human haematopoietic stem cells (HSCs), and why this fails in culture, have impeded the expansion of HSCs for transplantation1. Here we identify MLLT3 (also known as AF9) as a crucial regulator of HSCs that is highly enriched in human fetal, neonatal and adult HSCs, but downregulated in culture. Depletion of MLLT3 prevented the maintenance of transplantable human haematopoietic stem or progenitor cells (HSPCs) in culture, whereas stabilizing MLLT3 expression in culture enabled more than 12-fold expansion of transplantable HSCs that provided balanced multilineage reconstitution in primary and secondary mouse recipients. Similar to endogenous MLLT3, overexpressed MLLT3 localized to active promoters in HSPCs, sustained levels of H3K79me2 and protected the HSC transcriptional program in culture. MLLT3 thus acts as HSC maintenance factor that links histone reader and modifying activities to modulate HSC gene expression, and may provide a promising approach to expand HSCs for transplantation.

Suggested Citation

  • Vincenzo Calvanese & Andrew T. Nguyen & Timothy J. Bolan & Anastasia Vavilina & Trent Su & Lydia K. Lee & Yanling Wang & Fides D. Lay & Mattias Magnusson & Gay M. Crooks & Siavash K. Kurdistani & Hann, 2019. "MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment," Nature, Nature, vol. 576(7786), pages 281-286, December.
    • Handle: RePEc:nat:nature:v:576:y:2019:i:7786:d:10.1038_s41586-019-1790-2
    DOI: 10.1038/s41586-019-1790-2
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    Cited by:

    1. Matteo Maria Naldini & Gabriele Casirati & Matteo Barcella & Paola Maria Vittoria Rancoita & Andrea Cosentino & Carolina Caserta & Francesca Pavesi & Erika Zonari & Giacomo Desantis & Diego Gilioli & , 2023. "Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Shicheng Sun & Ali Motazedian & Jacky Y. Li & Kevin Wijanarko & Joe Jiang Zhu & Kothila Tharmarajah & Kathleen A. Strumila & Anton Shkaruta & L. Rayburn Nigos & Jacqueline V. Schiesser & Yi Yu & Paul , 2024. "Efficient generation of human NOTCH ligand-expressing haemogenic endothelial cells as infrastructure for in vitro haematopoiesis and lymphopoiesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Yosuke Komata & Akinori Kanai & Takahiro Maeda & Toshiya Inaba & Akihiko Yokoyama, 2023. "MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Brandon Hadland & Barbara Varnum-Finney & Stacey Dozono & Tessa Dignum & Cynthia Nourigat-McKay & Adam M. Heck & Takashi Ishida & Dana L. Jackson & Tomer Itkin & Jason M. Butler & Shahin Rafii & Cole , 2022. "Engineering a niche supporting hematopoietic stem cell development using integrated single-cell transcriptomics," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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