Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, Australia.
Blood Adv. 2019 Feb 26;3(4):681-691. doi: 10.1182/bloodadvances.2018023986.
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.
鉴定造血干细胞（HSCs）命运选择的决定因素对于改善 HSCs 的临床应用以及增强我们对正常和恶性造血生物学的理解至关重要。在这里，我们表明，高迁移率族 AT 钩 2（HMGA2）是一种非组蛋白染色体结合蛋白，在 HSCs 以及胎儿、新生儿和成人造血中最不成熟的祖细胞亚群中高度且优先表达。短发夹 RNA 敲低 HMGA2 会损害脐带血（CB）衍生的 CB CD34 细胞的长期造血重建。相反，HMGA2 在 CB CD34 细胞中的过表达导致在连续移植实验中整体增强重建，伴随着向巨核细胞-红细胞和髓系谱系的倾斜。RNA 测序分析表明，在 CD34 细胞中强制表达 HMGA2 会诱导与向巨核细胞-红细胞和髓系谱系分化以及与生长和存活相关的基因表达特征，这些特征在蛋白质水平上与 AKT 的强烈激活相关。总之，我们的研究结果表明 HMGA2 在调节人类 HSPCs 的增殖和分化中起着关键作用。
