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

Kumar, Praveen LU ; Beck, Dominik; Galeev, Roman LU ; Thoms, Julie A.I.; Talkhoncheh, Mehrnaz Safaee LU ; de Jong, Ineke LU ; Unnikrishnan, Ashwin; Baudet, Aurélie LU ; Subramaniam, Agatheeswaran LU and Pimanda, John E., et al. (2019) In Blood Advances 3(4). p.681-691
Abstract

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 CD34+ cells. Conversely, overexpression of HMGA2 in CB CD34+ cells led to overall enhanced reconstitution in serial transplantation assays accompanied by a... (More)

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 CD34+ cells. Conversely, overexpression of HMGA2 in CB CD34+ 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 CD34+ 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.

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published
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Blood Advances
volume
3
issue
4
pages
11 pages
publisher
American Society of Hematology
external identifiers
  • scopus:85062247370
ISSN
2473-9529
DOI
10.1182/bloodadvances.2018023986
language
English
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yes
id
cf8502b3-2c6a-43bd-9427-8d3c3dea2819
date added to LUP
2019-03-11 12:30:18
date last changed
2019-04-02 04:14:47
@article{cf8502b3-2c6a-43bd-9427-8d3c3dea2819,
  abstract     = {<p>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 CD34+ cells. Conversely, overexpression of HMGA2 in CB CD34+ 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 CD34+ 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.</p>},
  author       = {Kumar, Praveen and Beck, Dominik and Galeev, Roman and Thoms, Julie A.I. and Talkhoncheh, Mehrnaz Safaee and de Jong, Ineke and Unnikrishnan, Ashwin and Baudet, Aurélie and Subramaniam, Agatheeswaran and Pimanda, John E. and Larsson, Jonas},
  issn         = {2473-9529},
  language     = {eng},
  month        = {02},
  number       = {4},
  pages        = {681--691},
  publisher    = {American Society of Hematology},
  series       = {Blood Advances},
  title        = {HMGA2 promotes long-term engraftment and myeloerythroid differentiation of human hematopoietic stem and progenitor cells},
  url          = {http://dx.doi.org/10.1182/bloodadvances.2018023986},
  volume       = {3},
  year         = {2019},
}