High DNA-methyltransferase 3B expression predicts poor outcome in acute myeloid leukemia, especially among patients with co-occurring NPM1 and FLT3 mutations
Bibliographic record
Abstract
DNA methyltransferases (DNMTs) are epigenetic regulators targeted to the treatment of hematological malignancies.1, 2, 3, 4 Mutations in the DNA methyltransferase DNMT3A and high expression of its paralogue DNMT3B have been associated with inferior outcome in acute myeloid leukemia (AML) and other hematological malignancies.5, 6, 7, 8 Using a publicly available gene expression data set,9 we studied whether DNMT3B expression correlates with outcome in genetically well-defined AML subgroups. We first validated the expression data from the microarray by quantitative PCR, using 39 patient samples (Supplementary Figure S1A). DNMT3B micro-array analyses showed that the expression was not normally distributed among AML patients; in the quartile with highest expression, a larger variation in expression was observed compared to the three quartiles with relatively lower expression (Supplementary Figure S1B). The median DNMT3B expression in AML samples was significantly lower compared with that observed in normal bone marrow (NBM)-derived CD34+ cells (P 60 years; white blood cell counts >100 × 109/l; transplantation status; karyotypes t(8;21), t(15;17) and inv(16); nucleophosmin 1 (NPM1), FLT3-ITD, DNMT3A and double CEBPA mutations, and ecotropic viral integration site 1 (EVI1) overexpression), which revealed that higher DNMT3B expression carried an independent prognostic risk for both OS and EFS (hazard ratio (HR): 1.768, 95% confidence interval (CI): 1.384–2.260; P<0.001 and HR: 1.706, 95% CI: 1.342–2.168; P<0.001, respectively, Table 1), in line with a recently published study.7 In fact, higher DNMT3B expression showed a higher hazard ratio for OS than that of well-known adverse prognostic factors such as internal tandem duplications of the fms-related tyrosine kinase 3 (FLT3-ITD, HR: 1.675, 95% CI: 1.287–2.179; P<0.001) and overexpression of the EVI1 gene (HR: 1.430, 95% CI: 0.999–2.047; P=0.051).
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.008 |
| 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".