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

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 and Hanna K. A. Mikkola ()
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Vincenzo Calvanese: 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
Gay M. Crooks: University of California Los Angeles
Siavash K. Kurdistani: University of California Los Angeles
Hanna K. A. Mikkola: University of California Los Angeles

Nature, 2019, vol. 576, issue 7786, 281-286

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1790-2

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