Sowing the seeds of leukemia before birth

doi:10.1126/science.abj3957

GSTDTAP > 气候变化

DOI	10.1126/science.abj3957
	Sowing the seeds of leukemia before birth
	Irene Roberts; Paresh Vyas
	2021-07-09
发表期刊	Science
出版年	2021
英文摘要	Each year, ∼200,000 babies worldwide are born with Down syndrome (DS), owing to constitutional trisomy of chromosome 21 (T21) ([ 1 ][1]). Children with DS have a markedly increased risk of leukemia, particularly in their first 4 years. Almost 60,000 (30%) will harbor within their blood cells damaging, fetally acquired mutations in the transcription factor gene GATA binding protein 1 ( GATA1 ), which encodes a short GATA1 protein (GATA1s) and triggers the first step in the development of leukemia ([ 2 ][2]). GATA1 mutations are rare in disomic individuals and virtually never cause leukemia in the absence of T21. Why GATA1 mutations are so frequent in T21 babies and the mechanisms by which a supernumerary chromosome 21 (Hsa21) predisposes to, and cooperates with, genetic events in DS leukemogenesis are not known. On page 179 of this issue, Wagenblast et al. ([ 3 ][3]) identify Hsa21 microRNAs (miRNAs) that cooperate with GATA1s and map the cellular origin of the leukemia. Compared with children of the same age without DS, the risk of myeloid leukemia (modeled by Wagenblast et al. ) is 150-fold greater, whereas acute lymphoblastic leukemia is more than 20-fold higher in people with DS. DS also causes functional and developmental abnormalities in virtually all organs and tissues. Progressive cognitive impairment, dementia, and cardiac disease are major causes of ill health, with profound effects on the lives of patients and their families. How the supernumerary Hsa21 causes the clinical features of DS remains unclear. Wagenblast et al. use CRISPR-Cas9 editing of human fetal hematopoietic stem and progenitor cells (HSPCs) trisomic for Hsa21 to induce DS-specific leukemogenic deletions in GATA1 and stromal antigen 2 ( STAG2 ). These edited cells were then transplanted into immunocompromised mice, creating xenograft mouse models that faithfully recapitulate DS leukemia. In contrast to previous models, it seems likely that targeting primary human fetal HSPCs to induce the pathognomonic GATA1 mutations provided the permissive cellular substrate for transformation, as predicted by clinical and biological studies in DS ([ 2 ][2], [ 4 ][4], [ 5 ][5]). Whereas in disomic fetal cells, expression of GATA1s caused severe impairment of erythropoiesis (corresponding to anemia in non-DS individuals with germline GATA1 mutations), in T21 fetal cells, GATA1s expression increased megakaryocytes and leukemia-like blast cells similar to those in the preleukemia in DS babies ([ 2 ][2], [ 4 ][4]). ![Figure][6] Cooperating changes to initiate leukemia in fetal cells The supernumerary copy of human chromosome 21 in Down syndrome [trisomy 21 (T21)] perturbs fetal gene expression and hematopoietic stem and progenitor cell (HSPC) development. Acquisition of exon 2 mutations in the GATA binding protein 1 ( GATA1 ) gene in fetal T21 but not disomic HSPCs causes preleukemia in mice because of expression of a short GATA1 protein (GATA1s). Secondary mutations in GATA1s-expressing cells, such as in stromal antigen 2 ( STAG2 ), cause myeloid leukemia in disomic and T21 mouse fetal HSPCs. GRAPHIC: V. ALTOUNIAN/ SCIENCE Studies to decipher the molecular basis for the effects of T21 have generated a wealth of data from a range of cell types, most focusing on gene dosage of Hsa21-located genes. Hsa21, the smallest human chromosome, has ∼230 protein-coding genes and almost twice as many non–protein coding genes, including five miRNAs ([ 1 ][1], [ 6 ][7]). Although many Hsa21 genes are expressed at 1.5-fold higher levels than in matching disomic populations, this is highly tissue and cell population specific, and the overall effects of the supernumerary Hsa21 extend far beyond this. Almost all datasets show genome-wide perturbation of gene expression by T21. This likely explains, at least in part, why causative links between altered gene expression and phenotypes in DS have been so difficult to establish and why none of these phenotypes has so far been explained by a single gene acting alone. Studies aimed at narrowing the region(s) of Hsa21 responsible for specific phenotypes are often inconsistent and hampered by the rarity of individuals with DS owing to partial T21 (<1%) and by cellular systems that imperfectly capture the genetic and epigenetic complexity of DS. Given the importance of cell context, the development of a biologically accurate model, recreating the precise initiating step necessary for all DS myeloid leukemias (GATA1s-encoding mutation) in the precise cell type where this event occurs (fetal liver HSPCs), should allow more specific and tractable questions about the role of T21 to be addressed. Focusing on the mechanism of cooperation between T21 and GATA1s, Wagenblast et al. asked how binding of mutant GATA1s protein differed from full-length, wild-type GATA1 in fetal HSPCs. They found that GATA1s specifically bound to thousands of promoters, including those that regulate genes controlling miRNA production. They focused on three Hsa21 miRNA genes— MIR-125b-2, MIR-155 , and LET-7C —whose expression was up-regulated specifically in T21 long-term hematopoietic stem cells (LT-HSCs). Enforced overexpression of these miRNAs in normal fetal LT-HSCs mimicked some features of T21 cells, whereas ablating them partially reduced the preleukemic phenotype of GATA1s, suggesting that GATA1s-mediated up-regulation of these Hsa21 miRNAs' expression could partially explain the mechanism of GATA1s-induced preleukemia in DS. This adds DS myeloid leukemia to the list of human diseases, including other phenotypic abnormalities in DS, that may be caused by altered miRNA expression ([ 1 ][1]). The precise mechanisms underlying the distinct cooperation between T21 and GATA1s in human fetal cells remain enigmatic but are likely to include several Hsa21 genes with known roles in embryonic and fetal hematopoiesis, acting together in a cell context–dependent manner (see the figure). The reasons for the high frequency of somatic GATA1 mutations in DS fetal blood cells (most likely owing to selection) and why most GATA1 -mutant cells are rapidly cleared after birth—a feature not captured in Wagenblast et al. 's model, which may involve the T21 hematopoietic cell niche—are not yet known. Evidence of a mutagenic phenotype or generalized defect in DNA repair in DS tissues, including blood cells, is sparse. Children with DS have a lower than expected incidence of solid tumors, pointing to specific properties of T21 in hematopoietic cells. This might also explain why T21 appeared to be less relevant for postnatal progression of myeloid leukemia in Wagenblast et al. 's model. T21 is the most frequent constitutional aneuploidy compatible with survival into adulthood, although fetal loss is high ([ 1 ][1]). Yet, despite the importance of genome organization on function ([ 7 ][8]), the effects of aneuploidy on nuclear architecture of human fetal cells and subsequent consequences for gene expression and protein production are unknown. Similarly, the development of new model systems is needed to better understand the function of each element of Hsa21, only 48% of which has currently been mapped in detail ([ 1 ][1]). Moreover, it can be argued that the value of such models lies with the opportunities for improving outcomes for individuals with DS and their families. This will likely be realized through small steps in specific complications such as leukemia but could include bolder initiatives such as harnessing X chromosome inactivation in female cells by perhaps integrating an X inactive specific transcript ( XIST ) transgene to reduce Hsa21 transcriptional output back to disomic levels ([ 8 ][9]). 1. [↵][10]1. S. E. Antonarakis et al ., Nat. Rev. Dis. Primers 6, 9 (2020). [OpenUrl][11] 2. [↵][12]1. I. Roberts et al ., Blood 122, 3908 (2013). [OpenUrl][13][Abstract/FREE Full Text][14] 3. [↵][15]1. E. Wagenblast et al ., Science 373, eabf6202 (2021). [OpenUrl][16][Abstract/FREE Full Text][17] 4. [↵][18]1. A. Roy et al ., Proc. Natl. Acad. Sci. U.S.A. 109, 17579 (2012). [OpenUrl][19][Abstract/FREE Full Text][20] 5. [↵][21]1. M. Labuhn et al ., Cancer Cell 36, 123 (2019). [OpenUrl][22] 6. [↵][23]1. M. Hattori et al ., Nature 405, 311 (2000). [OpenUrl][24][CrossRef][25][PubMed][26][Web of Science][27] 7. [↵][28]1. C. Do, 2. Z. Xing, 3. Y. E. Yu, 4. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/334226
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Irene Roberts,Paresh Vyas. Sowing the seeds of leukemia before birth[J]. Science,2021.
APA	Irene Roberts,&Paresh Vyas.(2021).Sowing the seeds of leukemia before birth.Science.
MLA	Irene Roberts,et al."Sowing the seeds of leukemia before birth".Science (2021).