Prognostic Significance of a Short Sequence Insertion in the MCL-1 Promoter in Chronic Lymphocytic Leukemia
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Bibliographic record
Abstract
BACKGROUND: Mcl-1 protein contributes to the longevity of chronic lymphocytic leukemia (CLL) B cells, and its higher expression has been associated with resistance to chemotherapy. We sought structural changes in the MCL-1 gene in CLL patients and associated these with clinical parameters of the disease. METHODS: The MCL-1 gene from peripheral blood lymphocytes from 58 CLL patients and 18 control subjects and from the RL and BC-3 lymphoma cell lines was sequenced. Mcl-1 mRNA expression (in 20 consecutive patients and four control subjects) was analyzed by RNase protection assay, and Mcl-1 protein expression (in 18 consecutive patients and four controls) was analyzed by western blotting. Genetic changes in MCL-1 were associated with biochemical and clinical characteristics, including expression of CD38, a negative prognostic factor. Cox proportional hazards modeling was used to determine the prognostic importance of changes in the MCL-1 gene, and the Kaplan-Meier method was used to analyze patient survival. All statistical tests were two sided. RESULTS: A 6- or 18-nucleotide sequence insertion was found in the same site in the MCL-1 promoter in 17 of 58 patients and in BC-3 cells; it was absent in all control subjects and in RL cells. Of 21 CD38-negative patients, 10 had a promoter insertion; of 17 CD38-positive patients, one had a promoter insertion (P =.0099). Patients with a promoter insertion had higher mRNA (median = 26.8 relative units, interquartile range [IQR] = 14.9 to 35.2, versus median = 8.8 relative units, IQR = 3.9 to 15.7, P =.030, U-test) and protein (median = 0.84 relative units, IQR = 0.81 to 1.0 versus median = 0.47, IQR = 0.32 to 0.70, P =.021, U-test) expression, more rapid disease progression (P =.012), poorer response to chemotherapy (P =.001), and shorter overall (P =.0088) and disease-specific (P <.001) survival than patients with a normal promoter. The presence of an MCL-1 promoter insertion had prognostic significance in a Cox model (P =.001). CONCLUSIONS: The MCL-1 promoter insertion may identify a high-risk group of CD38-negative CLL patients.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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 it