Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21

Abstract

The 40-fold increase in childhood megakaryocyte-erythroid and B-cell leukemia in Down syndrome implicates trisomy 21 (T21) in perturbing fetal hematopoiesis. Here, we show that compared with primary disomic controls, primary T21 fetal liver (FL) hematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors are markedly increased, whereas granulocyte-macrophage progenitors are reduced. Commensurately, HSC and megakaryocyte-erythroid progenitors show higher clonogenicity, with increased megakaryocyte, megakaryocyte-erythroid, and replatable blast colonies. Biased megakaryocyte-erythroid-primed gene expression was detected as early as the HSC compartment. In lymphopoiesis, T21 FL lymphoid-primed multipotential progenitors and early lymphoid progenitor numbers are maintained, but there was a 10-fold reduction in committed PreproB-lymphoid progenitors and the functional B-cell potential of HSC and early lymphoid progenitor is severely impaired, in tandem with reduced early lymphoid gene expression. The same pattern was seen in all T21 FL samples and no samples had GATA1 mutations. Therefore, T21 itself causes multiple distinct defects in FL myelo-and lymphopoiesis.transient myeloproliferative disorder | aneuploidy | human fetus C onstitutional trisomy 21 (T21) causes Down syndrome (DS), the most common syndrome-associated chromosomal anomaly in humans (1). As well as with neurodevelopmental, cardiac, and gut anomalies (2), there is a striking increase in childhood acute leukemia in DS, even though the risk of solid tumors is much lower than with the general population (3). Intriguingly, this susceptibility to hematopoietic tumors manifests as an increased risk both of acute megakaryocyte (MK)-erythroid leukemia (known as ML-DS) by 150-fold and of acute B-lymphoblastic leukemia (B-ALL) by 33-fold (3, 4).DS leukemias display distinct characteristics that support a crucial role for T21 in their pathogenesis. Hallmarks of ML-DS are the megakaryoblastic phenotype, clinical presentation confined to the first 5 y of childhood (5, 6), an antecedent clonally linked preleukemic condition (termed transient myeloproliferative disorder, TMD) in most cases, and acquired N-terminal truncating mutations in the erythroid-MK transcription factor GATA1 (7-9). Such mutations in GATA1 are present in both ML-DS and TMD (9) but are not found in patients without DS who develop megakaryoblastic leukemia (7) and are not leukemogenic in the absence of T21 (10).Molecular, biologic, and clinical data indicate that TMD is initiated before birth (9,(11)(12)(13)(14). We previously reported that by the second trimester, the T21 fetal liver (FL) myeloid progenitor compartment is abnormal and that this occurs in the absence of GATA1 mutation (11, 12). Specifically, the MK-erythroid progenitor (MEP) population is expanded with increased cell-intrinsic MK and erythroid lineage proliferation from CD34 + cells. These data suggest that T21-mediated developmental alterations to FL myeloid progenitor development provide a cell-specific substrate for...

Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus

“…While the current study focuses on the role of GATA1s mutations in erythropoiesis, our findings also provide insights into how these mutations interact with T21. Previous work has shown that T21 augments erythropoiesis in primary fetal cells (61)(62)(63) and iPSCs (18,64). Here, we confirm these findings in T21/WT GATA1 iPSCs and demonstrate that GATA1s overrides the erythropoietic effects of T21 in isogenic double-mutant T21/GATA1s iPSCs derived from 2 different patients with TMD.…”

Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

“…Defects specific to certain aneuploidies as well as defects observed in all aneuploid strains analyzed were evident in our aneuploid HSCs. The lineage-specific defects such as reduced B-cell number observed in trisomy 16 FL-HSC reconstitutions are likely due to chromosome-specific effects, as B-cell differentiation defects have also been observed in DS (Roy et al 2012;Lane et al 2014). Furthermore, we observed decreased proliferative potential in all aneuploidy models that we examined.…”

Human haematopoietic stem cell development: from the embryo to the dish

“…Various haematopoietic diseases originate prenatally (Hunger et al, 1998;Greaves, 2005;Hong et al, 2008;Roy et al, 2012;Barrett et al, 2016), and oncogenic mutations in developing haematopoietic progenitors or stem cells can lead to pre-leukaemic changes that may not be manifested if the oncogene is activated in the adult counterparts (Barrett et al, 2016). The molecular mechanisms that regulate development and maintenance of haematopoietic progenitor and stem cells in the embryo differ significantly from those in the adult, and the functional heterogeneity that appears within the emerging HSC population during development further complicates our understanding of HSC regulation (Copley et al, 2012;Crisan et al, 2015;Beaudin et al, 2016).…”