Elevated Expression of miR-181a and miR-155 Identify Pediatric AML Patients at High Risk of Induction Failure, A Report from Children's Oncology Group.
Bibliographic record
Abstract
Abstract Abstract 2388 Acute myeloid leukemia (AML) is characterized by genomic abnormalities that impair differentiation and promote proliferation. There are known karyotypic alterations and somatic mutations associated with relapse risk, but are rarely predictive of response to induction chemotherapy. miRNAs are epigenetic regulators of cell cycle progression and proliferation and their altered expression can play roles in malignancy and cancer cell behavior. Aberrant expression of miRNAs has been implicated in AML pathogenesis and unique expression profiles have been established in specific subsets. Altered miR-181a and miR-155 expression was reported to correlate with specific cytogenetic and molecular characteristics and with clinical outcome. We inquired whether expression of miR-155 and miR-181a correlates with disease characteristics and clinical response in childhood AML. We evaluated diagnostic specimens from 175 AML patients with normal karyotype (NK) treated on COG AML trial AAML0531 for expression of the miRNAs by quantitative TaqMan MicroRNA Assays normalized against normal marrow. There was a 4 log-fold variation in miR-181a, and a 3 log-fold variation in miR-155 expression levels. Patients were divided into 4 quartiles (Q1-Q4) with Q1 consisting of patients with the lowest, and Q4 with the highest expression levels of the specific miRNA. We then correlated disease characteristics and clinical response across quartiles. There was no association of miR-181a or miR-155 expression with age, gender or race. For miR-155, patients in Q4 had a higher diagnostic WBC% than those in Q1-Q3 (60.4 vs. 23.3, p=0.003). Diagnostic bone marrow blast% for Q4 vs. Q1-Q3 was 83% vs. 65% (p=0.004). There was no correlation between miR-181a expression, for either diagnostic WBC (p=0.117) or bone marrow blast % (p=0.237). High miR-155 expression was accompanied by increased prevalence of FLT3-ITD mutations. 78% of patients in Q4 were FLT3-ITD+ vs. 27% in Q1-Q3 (p < 0.001). miR-155 expression was not associated with mutations in CEBPA (p=0.76), NPM1 (p=0.98) or WT1 (p=0.57) genes. With the high prevalence of FLT3-ITD, elevated miR-155 expression was associated with high-risk disease, where 50% in Q4 had high-risk disease vs. 12% in the Q1-Q3 (p<0.001). High miR-155 expression was inversely associated with low-risk disease.18% in Q4 had low-risk disease vs. 40% in Q1-Q3 (p=0.009). miR-155 expression was correlated with response to induction chemotherapy. Of patients in Q4, 58% achieved a morphologic complete remission (CR) vs. 81% in Q1-Q3 (p=0.003). As FLT3-ITD is highly prevalent in Q4, we inquired if miR-155 expression correlated with response to induction therapy in FLT3-ITD- patients. FLT3-ITD- patients in Q4 had a 44% CR rate vs. 86% in Q1-Q3 (p=0.008), suggesting that in addition to its association with FLT3-ITD, miR-155 expression may independently provide data on potential response to chemotherapy. Evaluation of miR-181a expression demonstrated that prevalence of CEBPA mutations increased with increasing miR-181a expression and 40% of patients in Q4 were CEBPA+ vs. 7% in Q1-Q3 (p < 0.001). There was no association between miR-181a expression and FLT3-ITD (p=0.727), NPM1 (p=0.466) or WT1 (p=0.701) mutations. High miR-181a expression was highly associated with low-risk disease, with 57% in Q4 categorized as low risk vs. 27% in Q1-Q3 (p<0.001). miR-181a expression was not associated with response to induction chemotherapy (CR 80% in Q4 vs. 74% in Q1-Q3, p=0.43). Remission induction rate was re-evaluated after exclusion of CEBPA+ patients. Expression levels had no effect on CR rate (p=0.62). However, of patients in Q4, 71% had evidence of minimal residual disease (MRD) vs. 36% in Q1-Q3 (p=0.003). The correlation of miR-181a expression and MRD remained significant even after exclusion of FLT3-ITD, NPM1 and CEBPA mutations (MRD of 86% vs. 31%, p=0.01). We demonstrate significant association of miR-155 and miR-181a expression with specific disease characteristics and clinically significant mutations in pediatric AML. We also show that elevated expression is highly predictive of induction failure, providing potential biomarkers for identifying patients at high risk of poor response prior to therapy. miRNA expression could provide clinically significant information for use in therapeutic allocation. Validation of this finding in a larger cohort of pediatric and adult patients is underway. Disclosures: Loken: Hematologics, Inc: Employment, Equity Ownership. Pardo:Hematologics Inc: Employment.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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".