HMGA2 promotes long-term engraftment and myeloerythroid differentiation of human hematopoietic stem and progenitor cells

Kumar, P; Beck, D; Galeev, R; Thoms, JAI; Talkhoncheh, MS; de Jong, I; Unnikrishnan, A; Baudet, A; Subramaniam, A; Pimanda, JE; Larsson, J

HMGA2 promotes long-term engraftment and myeloerythroid differentiation of human hematopoietic stem and progenitor cells

Kumar, P Beck, D Galeev, R Thoms, JAI Talkhoncheh, MS de Jong, I Unnikrishnan, A Baudet, A Subramaniam, A Pimanda, JE Larsson, J

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Publication Type:: Journal Article
Citation:: Blood Advances, 2019, 3 (4), pp. 681 - 691
Issue Date:: 2019-02-26

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Field	Value	Language
dc.contributor.author	Kumar, P	en_US
dc.contributor.author	Beck, D	en_US
dc.contributor.author	Galeev, R	en_US
dc.contributor.author	Thoms, JAI	en_US
dc.contributor.author	Talkhoncheh, MS	en_US
dc.contributor.author	de Jong, I	en_US
dc.contributor.author	Unnikrishnan, A	en_US
dc.contributor.author	Baudet, A	en_US
dc.contributor.author	Subramaniam, A	en_US
dc.contributor.author	Pimanda, JE	en_US
dc.contributor.author	Larsson, J	en_US
dc.date.available	2019-01-29	en_US
dc.date.issued	2019-02-26	en_US
dc.identifier.citation	Blood Advances, 2019, 3 (4), pp. 681 - 691	en_US
dc.identifier.issn	2473-9529	en_US
dc.identifier.uri	http://hdl.handle.net/10453/135422
dc.description.abstract	© 2019 by The American Society of Hematology. Identification of determinants of fate choices in hematopoietic stem cells (HSCs) is essential to improve the clinical use of HSCs and to enhance our understanding of the biology of normal and malignant hematopoiesis. Here, we show that high-mobility group AT hook 2 (HMGA2), a nonhistone chromosomal-binding protein, is highly and preferentially expressed in HSCs and in the most immature progenitor cell subset of fetal, neonatal, and adult human hematopoiesis. Knockdown of HMGA2 by short hairpin RNA impaired the long-term hematopoietic reconstitution of cord blood (CB)–derived CB CD341 cells. Conversely, overexpression of HMGA2 in CB CD341 cells led to overall enhanced reconstitution in serial transplantation assays accompanied by a skewing toward the myeloerythroid lineages. RNA-sequencing analysis showed that enforced HMGA2 expression in CD341 cells induced gene-expression signatures associated with differentiation toward megakaryocyte-erythroid and myeloid lineages, as well as signatures associated with growth and survival, which at the protein level were coupled with strong activation of AKT. Taken together, our findings demonstrate a key role of HMGA2 in regulation of both proliferation and differentiation of human HSPCs.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/APP1073768
dc.relation.ispartof	Blood Advances	en_US
dc.relation.isbasedon	10.1182/bloodadvances.2018023986	en_US
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.subject.mesh	Hematopoietic Stem Cells	en_US
dc.subject.mesh	Cells, Cultured	en_US
dc.subject.mesh	Erythroid Cells	en_US
dc.subject.mesh	Myeloid Cells	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice, SCID	en_US
dc.subject.mesh	HMGA2 Protein	en_US
dc.subject.mesh	Hematopoietic Stem Cell Transplantation	en_US
dc.subject.mesh	Hematopoiesis	en_US
dc.subject.mesh	Cell Proliferation	en_US
dc.subject.mesh	Up-Regulation	en_US
dc.title	HMGA2 promotes long-term engraftment and myeloerythroid differentiation of human hematopoietic stem and progenitor cells	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	3	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Strength - AAI - Advanced Analytics Institute Research Centre
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	in_progress	*
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	3	en_US

Abstract:

© 2019 by The American Society of Hematology. Identification of determinants of fate choices in hematopoietic stem cells (HSCs) is essential to improve the clinical use of HSCs and to enhance our understanding of the biology of normal and malignant hematopoiesis. Here, we show that high-mobility group AT hook 2 (HMGA2), a nonhistone chromosomal-binding protein, is highly and preferentially expressed in HSCs and in the most immature progenitor cell subset of fetal, neonatal, and adult human hematopoiesis. Knockdown of HMGA2 by short hairpin RNA impaired the long-term hematopoietic reconstitution of cord blood (CB)–derived CB CD341 cells. Conversely, overexpression of HMGA2 in CB CD341 cells led to overall enhanced reconstitution in serial transplantation assays accompanied by a skewing toward the myeloerythroid lineages. RNA-sequencing analysis showed that enforced HMGA2 expression in CD341 cells induced gene-expression signatures associated with differentiation toward megakaryocyte-erythroid and myeloid lineages, as well as signatures associated with growth and survival, which at the protein level were coupled with strong activation of AKT. Taken together, our findings demonstrate a key role of HMGA2 in regulation of both proliferation and differentiation of human HSPCs.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/135422