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

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HMGA2 promotes long-term engraftment and myeloerythroid differentiation of human hematopoietic stem and progenitor cells. / Kumar, Praveen; Beck, Dominik; Galeev, Roman; Thoms, Julie A.I.; Talkhoncheh, Mehrnaz Safaee; de Jong, Ineke; Unnikrishnan, Ashwin; Baudet, Aurélie; Subramaniam, Agatheeswaran; Pimanda, John E.; Larsson, Jonas.

In: Blood Advances, Vol. 3, No. 4, 26.02.2019, p. 681-691.

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T1 - HMGA2 promotes long-term engraftment and myeloerythroid differentiation of human hematopoietic stem and progenitor cells

AU - Kumar, Praveen

AU - Beck, Dominik

AU - Galeev, Roman

AU - Thoms, Julie A.I.

AU - Talkhoncheh, Mehrnaz Safaee

AU - de Jong, Ineke

AU - Unnikrishnan, Ashwin

AU - Baudet, Aurélie

AU - Subramaniam, Agatheeswaran

AU - Pimanda, John E.

AU - Larsson, Jonas

PY - 2019/2/26

Y1 - 2019/2/26

N2 - 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.

AB - 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.

U2 - 10.1182/bloodadvances.2018023986

DO - 10.1182/bloodadvances.2018023986

M3 - Article

C2 - 30808686

AN - SCOPUS:85062247370

VL - 3

SP - 681

EP - 691

JO - Blood Advances

JF - Blood Advances

SN - 2473-9529

IS - 4

ER -