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

Autor:	Kumar P; Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden., Beck D; Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, Australia.; Centre for Health Technologies and.; School of Software, University of Technology Sydney, Sydney, NSW, Australia; and., Galeev R; Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden., Thoms JAI; Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, Australia., Talkhoncheh MS; Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden., de Jong I; Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden., Unnikrishnan A; Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, Australia., Baudet A; Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden., Subramaniam A; Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden., Pimanda JE; Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, Australia.; Department of Haematology, Prince of Wales Hospital, Sydney, NSW, Australia., Larsson J; Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2019 Feb 26; Vol. 3 (4), pp. 681-691.
DOI:	10.1182/bloodadvances.2018023986
Abstrakt:	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. (© 2019 by The American Society of Hematology.)
Databáze:	MEDLINE
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