Functional and Molecular Consequences of Trisomy 21 on Human Fetal Hematopoiesis
Bibliographic record
Abstract
Abstract Children with Down Syndrome (DS) are at 150-fold increased risk of developing acute megakaryoblastic leukemia (ML-DS) and 33-fold increased risk of acute B-lymphoblastic leukemia. The multistep pathogenesis of DS - associated pre-leukemia and subsequent progression to ML-DS is among the most well characterized human blood malignancies. Trisomy 21 fetal liver (FL) provides a tractable model for dissecting T21-mediated pre-leukemic changes in human HSPC. Using a recently published (Notta, F. et. al., Science 2016) enhanced sorting scheme for human blood progenitors and paired normal disomic and trisomic human FL samples, we sought a more thorough understanding of the molecular and functional perturbations associated with T21 in human FL hematopoiesis by: 1) assessing the proportional frequency/absolute numbers of 12 normal and T21 FL HSPC populations, 2) examining clonal, proliferative and lineage output using single cell stroma-based myelo-erythroid (ME) and myelo-lymphoid (ML) differentiation assays, 3) performing RNA seq and ATAC seq to elucidate variations in gene expression and epigenetic alterations, 4) and generating long-term clonal xenografts from highly purified normal and T21 FL HSC followed by secondary transplantation to uncover alterations in HSC frequency, lineage output and progenitor hierarchy. Flow cytometry was performed on 4 sets of paired, gestational stage matched disomic and trisomic human fetal liver CD34+ HSPC samples to assess changes in the proportional frequency/absolute numbers of 12 HSCP populations. Our results reveal that the T21 FL hierarchy exhibits increased frequencies of HSC, LMPP, MPP F2/F3, CMP F3 and MEP F3 populations and concomitantly decreased MPP F1, CMP F1, MEP F1 and GMP populations. To assess T21-induced functional changes at the clonal level, we utilized single cell stroma-based differentiation assays. In ME assays, we observed increased Mk lineage output while oligopotent lineage output (M/E/Mk) was found to be skewed into the CD34+CD38+ compartment. Single cell ML assays demonstrated a loss of B lineage differentiation potential and greatly reduced NK lineage output that resulted in a complete loss of oligopotent clones (B/NK/M) in HSC, MPP F1 and LMPP. Despite observing increased numbers of immunophenotypic HSC in T21 FL samples, in vivo LDA xenotransplantation of highly purified CD34+CD38-CD90+CD45RA-CD49f+ HSC showed no change in the frequency of functional T21 FL HSC. Compared to control, T21 HSC produced smaller hCD45+ grafts with increased CD33+ myeloid, CD41+ Mk and platelet frequencies and reduced GlyA+ erythroid frequency. Furthermore, T21 grafts demonstrated an inverted CD14+ monocyte/CD66b+ granulocyte ratio with almost complete loss of CD66b+CD16+CD49d- neutrophils. Initial RNA seq results from highly purified disomic and trisomic HSC and MPP reveal aberrant expression of genes from pathways not previously implicated in T21 associated malignancies. These data suggest that T21 induces relatively consistent alterations in population frequency across the FL blood progenitor hierarchy. Furthermore, our data suggests that T21 FL HSC are biased toward E, M, Mk lineage fates at the expense of B, T, NK and neutrophil fates. Overall, our work provides unique and previously unrecognized insights into the pathogenesis of DS-associated leukemia. Disclosures No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".