Niche Requirements of Transient Leukemia Cells in Down Syndrome
Bibliographic record
Abstract
Abstract Abstract 1753 Background. Young children with Down syndrome (DS; constitutional trisomy 21) have a 150-fold higher risk of developing acute myeloid leukemia (AML). Blast cells are detectable in the peripheral blood of approximately 10% of newborns with DS; these indicate the frequent presence of a preleukemic disorder termed transient leukemia (TL)/transient myeloproliferative disorder (TMD). This disorder of fetal hematopoiesis is triggered by somatic mutations of the hematopoietic transcription factor GATA1 exclusively in the context of cellular trisomy 21. The majority of TL cases undergo spontaneous resolution by unknown mechanisms. In contrast, approximately 1 of 5 cases progress to AML within a defined postnatal window (first 4 years of life). We hypothesized that the resolution of TL results from the absence of essential environmental cues following the developmental transition from prenatal fetal liver (FL) hematopoiesis to postnatal blood cell formation in the bone marrow (BM). We previously observed that primary blasts of human TL lack the proliferative expansion in the bone marrow environment of xenotransplant recipients that is observed for blasts of DS-AML. Consequently, we aimed to identify the signals provided by the FL niche that support the survival and proliferation of human TL cells. Methods and Results. To determine the differential impact of the hematopoietic niche provided by FL and postnatal BM on TL cells, we cultured primary human TL cells on murine stromal cell lines that were derived either from FL (AFT024) or adult BM (MS-5). The absolute number of primary TL cells increased >80-fold during culture on FL-derived stromal cells for 2 weeks. In contrast, BM-derived MS-5 stromal cells supported only a moderate expansion (<10-fold), which was associated with enhanced induction of apoptotic cell death and evidence of partial myeloid differentiation. Direct interaction between TL and stromal cells – acting co-operatively with soluble growth factors – appears indispensable for the maintenance of TL cell survival and stimulation of proliferation. Functional studies identified the very late antigen-4 [VLA-4 (CD49d)]/vascular cell adhesion molecule-1 (VCAM-1) binding partners as putative mediator of this interaction. Furthermore, insulin-like growth factor 2 (IGF-2) supplementation augmented the proliferation of TL cells specifically in the context of the FL niche. Neither IGF-2 alone or in combination with BM-derived stroma promoted expansion of TL cells. Work currently underway aims at identification of additional molecular pathways involved in TL-cell regulation, including elucidating the potential role of Notch signaling in development and maintenance of TL cells. Conclusions. Cooperative signals that are preferentially provided by the hematopoietic environment of the fetal liver support the survival and proliferation of human TL cells. These signals consist of a combination of cell-cell contact, in part mediated by VLA-4/ VCAM1, and soluble growth factors such as IGF-2. The identification and disruption of signaling pathways that are essential for the survival and expansion of TL blasts has the potential to prevent development of AML in children with Down syndrome by targeted elimination of the preleukemic TL clone. 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) | 0.001 | 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".