Cellular and molecular architecture of hematopoietic stem cells and progenitors in genetic models of bone marrow failure
Bibliographic record
Abstract
Inherited bone marrow failure syndromes, such as Fanconi anemia (FA) and Shwachman-Diamond syndrome (SDS), feature progressive cytopenia and a risk of acute myeloid leukemia (AML). Using deep phenotypic analysis of early progenitors in FA/SDS bone marrow samples, we revealed selective survival of progenitors that phenotypically resembled granulocyte-monocyte progenitors (GMP). Whole-exome and targeted sequencing of GMP-like cells in leukemia-free patients revealed a higher mutation load than in healthy controls and molecular changes that are characteristic of AML: increased G>A/C>T variants, decreased A>G/T>C variants, increased trinucleotide mutations at Xp(C>T)pT, and decreased mutation rates at Xp(C>T)pG sites compared with other Xp(C>T)pX sites and enrichment for Cancer Signature 1 (X indicates any nucleotide). Potential preleukemic targets in the GMP-like cells from patients with FA/SDS included SYNE1, DST, HUWE1, LRP2, NOTCH2, and TP53. Serial analysis of GMPs from an SDS patient who progressed to leukemia revealed a gradual increase in mutational burden, enrichment of G>A/C>T signature, and emergence of new clones. Interestingly, the molecular signature of marrow cells from 2 FA/SDS patients with leukemia was similar to that of FA/SDS patients without transformation. The predicted founding clones in SDS-derived AML harbored mutations in several genes, including TP53, while in FA-derived AML the mutated genes included ARID1B and SFPQ. We describe an architectural change in the hematopoietic hierarchy of FA/SDS with remarkable preservation of GMP-like populations harboring unique mutation signatures. GMP-like cells might represent a cellular reservoir for clonal evolution.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".