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

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 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.

Identification of the Effects of Aspirin and Sulindac Sulfide on the Inhibition of HMGA2-Mediated Oncogenic Capacities in Colorectal Cancer

“…In the left panel of Figure 1 , gene expression profiles from HMGA2 -knockdown of human esophageal cancer cells (TE-8) derived from the GEO dataset, GSE143882, are displayed. In the right panel of Figure 1 , gene expression profiles from HMGA2 overexpression of hematopoietic stem and progenitor cells (HSPCs) derived from the GEO dataset, GSE107594, are shown [ 15 ]. Furthermore, the top 100 differentially expressed genes (DEGs) from the two GEO datasets were analyzed and queried using the Library of Integrated Network-Based Cellular Signatures (LINCS) L1000 platform to predict which drugs might have potency to inhibit HMGA2 expression.…”

HMGA Proteins in Stemness and Differentiation of Embryonic and Adult Stem Cells

“…This can be explained by considering that mouse ESCs behave differently from human ESCs that actually resemble mouse EpiLCs in which Hmga2 starts to be expressed [30] and where its function needs to be better described. In adult stem cells, where HMGA2 is highly expressed in both humans and mice, this protein seems to be required to allow self-renewal and to block differentiation [5,38,42,43,45,[47][48][49]. However, the decline of HMGA2 during the differentiation of adult stem cells has to be tightly controlled to allow efficient differentiation [5,45,[47][48][49].…”

“…A detailed analysis of the HMGA2 contribution to human HSC differentiation showed that the suppression of HMGA2 leads to a decrease of myeloid progenitor cells but has no effects on the differentiation of these cells. On the contrary, HMGA2 is necessary for both erythroid precursor propagation and differentiation [45]. Of note, Calvazzana-Calvo and colleagues described a crucial role of HMGA2 in the hematopoietic compartment.…”

HMGA Genes and Proteins in Development and Evolution

“…HMGA2 overexpression in transgenic mice induced proliferative hematopoiesis and clonal expansion of hematopoietic stem cells (HSCs), with increase of pStat5 and pAKT levels [175,180]. HMGA2 is involved in both proliferation and differentiation of human hematopoietic stem and progenitor cells [181].…”