Prognostic Significance of a Short Sequence Insertion in the MCL-1 Promoter in Chronic Lymphocytic Leukemia
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.
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 | 0.002 |
| 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".