Impaired DNA damage response and inflammatory signalling underpins hematopoietic stem cell defects in <i>Gata2</i> haploinsufficiency
Bibliographic record
Abstract
Abstract Clinical GATA2 deficiency syndromes arise from germline haploinsufficiency inducing mutations in GATA2 , resulting in immunodeficiency that evolves to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). How GATA2 haploinsufficiency disrupts the function and transcriptional network of hematopoietic stem/progenitors (HSCs/HSPCs) to facilitate the shift from immunodeficiency to pre-leukemia is poorly characterised. Using a conditional mouse model harboring a single allele deletion of Gata2 from the start of HSC development in utero , we identified pervasive defects in HSPC differentiation from young adult Gata2 haploinsufficient mice during B-cell development, early erythroid specification, megakaryocyte maturation to platelets and inflammatory cell generation. Gata2 haploinsufficiency abolished HSC self-renewal and multi-lineage differentiation capacity. These functional alterations closely associated with deregulated DNA damage responses and inflammatory signalling conveyed from Gata2 haploinsufficient HSCs. We identified genetic interplay between Gata2 and Asxl1 , a driver of DNA damage and inflammation and, notably, a recurrent secondary mutation found in GATA2 haploinsufficiency disease progression to MDS/AML. shRNA mediated knockdown of Asxl1 in Gata2 haploinsufficient HSPCs led to an enhanced differentiation block in vitro . By analysis of HSCs from young adult compound Gata2/Asxl1 haploinsufficient mice, we discovered hyperproliferation of double haploinsufficient HSCs, which were also functionally compromised in transplantation compared to their single Gata2 or Asxl1 haploinsufficient counterparts. Through both Gata2/Asxl1 dependent and unique transcriptional programs, HSCs from compound Gata2/Asxl1 haploinsufficient fortified deregulated DNA damage responses and inflammatory signalling initiated in Gata2 haploinsufficient HSCs and established a broad pre-leukemic program. Our data reveal how Gata2 haploinsufficiency initially drives deregulation of HSC genome integrity and suggest the mechanisms of how secondary mutations like ASXL1 take advantage of HSC genomic instability to nurture a pre-leukemic state in GATA2 haploinsufficiency syndromes.
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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".