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; Hanna K A Mikkola

doi:10.1038/s41586-019-1790-2

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

Nature. 2019 Dec;576(7786):281-286. doi: 10.1038/s41586-019-1790-2. Epub 2019 Nov 27.

Authors

Vincenzo Calvanese^{1

2}, Andrew T Nguyen³, Timothy J Bolan³, Anastasia Vavilina³, Trent Su⁴, Lydia K Lee⁵, Yanling Wang³, Fides D Lay³, Mattias Magnusson^{3

6}, Gay M Crooks^{6

7

8}, Siavash K Kurdistani^{6

4

8

9}, Hanna K A Mikkola^{10

11

12

13}

Affiliations

¹ Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA. vincalv@gmail.com.
² Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. vincalv@gmail.com.
³ Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
⁴ Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
⁵ Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, CA, USA.
⁶ Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA.
⁷ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.
⁹ Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA.
¹⁰ Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA. hmikkola@mcdb.ucla.edu.
¹¹ Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. hmikkola@mcdb.ucla.edu.
¹² Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. hmikkola@mcdb.ucla.edu.
¹³ Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. hmikkola@mcdb.ucla.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Self Renewal*
Cells, Cultured
Gene Expression Regulation
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells / cytology*
Hematopoietic Stem Cells / metabolism*
Humans
Mice
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Protein Binding

Substances

MLLT3 protein, human
Mllt3 protein, mouse
Nuclear Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding