A Variant Allele of the Gene Growth Factor Independence 1 (GFI1) Is Associated with Acute Myeloid Leukemia.
Bibliographic record
Abstract
Abstract Acute myeloid leukemia (AML) is characterized by an impaired differentiation and abnormal growth of myeloid-progenitor cells, resulting in an accumulation of malignant blast cells in the bone marrow. It represents 1% of all malignancies with overall incidence of 4.5 per 100 000 adults. About 10% of AML patients carry a chromosomal translocation t(8;21) that leads to the production of an AML1/ETO fusion protein. We have previously shown that mice lacking the transcription factor Gfi1 (Growth factor independent 1) show an accumulation of aberrant myelo-monocytic cells reminiscent of myeloproliferative disorders in patients and that Gfi1 is required to maintain the self-renewal and differentiation capability of hematopoietic stem cells. We show here that a variant allele of the gene encoding the transcriptional repressor GFI1, (GFI136N), is associated with AML in three independent Caucasians patient cohorts with an odds-ratio of 2.89 (p=2 x 10–5). The GFI136N variant occurred in 469 AML patients with an allele frequency of 0.064 compared to 0.023 in 503 healthy controls. Patients homozygous for the common form of GFI1 (GFI136S) and patients either heterozygous or homozygous for GFI136N did not differ with regard to the occurrence of AML with specific FAB subtypes, cytogenetic findings or Nucleophosmin 1 mutations. The variant GFI136N did not alter disease progression of AML overall, but correlated with a worse prognosis for patients carrying the t(8;21) chromosomal translocation. Here, the 5 year survival rate was 64% for GFI136S homozygous patients compared to 40% for patients carrying at least one allele of GFI136N. The sub-nuclear localization of GFI136S or GFI136N was different when transiently expressed in 3T3 cells. GFI136S was located mainly at the nuclear border, whereas GFI136S was distributed in a dotted pattern in the nucleus. In addition, we found that GFI136S, but not the variant GFI136N protein co-localized with AML1/ETO in the nucleus. Both GFI136S and GFI136N were able to repress transcription in established reporter gene assays. However, whereas AML/ETO was able to inhibit this activity of GFI136S, the variant GFI136N form was refractory to this inhibition by AML1/ETO, suggesting that the AML1/ETO-GFI1 interaction may be one of the factors responsible for a favorable outcome of t(8;21) positive AML. Our study indicates that the GFI136N variant allele may serve as a novel genetic marker to measure genetic predisposition for the development of AML and provides a first indication that this specific genetic variation at the Gfi1 locus affects the clinical outcome of t(8;21) positive AML patients.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".