High XBP1 expression is a marker of better outcome in multiple myeloma patients treated with bortezomib
Bibliographic record
Abstract
Multiple myeloma (MM) is a hematologic tumor characterized by accumulation of monoclonal plasma cells (PCs) in the bone marrow (BM) producing antigen-specific immunoglobulins. The transcription factor X box binding protein 1 (XBP1), the interferon regulatory factor 4 (IRF4) and the transcriptional repressor B lymphocite-induced maturation protein 1 (BLIMP1) are essential to drive physiological plasmacytic differentiation. 1,2 XBP1 is particularly required for the last stages of B-cell differentiation into PC, and, consistently, XBP1-deficient mice display normal Blymphocite development up to germinal center, but are unable to produce PCs. 2 High mRNA levels of IRF4, BLIMP1 and XBP1 have been detected in malignant PC and are negative prognostic factors in patients treated with standard chemotherapy or thalidomide. Lenalidomide seems to overcome the negative prognostic impact of IRF4 overexpression, due to its rapid downregulation following treatment. Bortezomib induces better responses in patients with high levels of XBP1. assessed the prognostic role of gene-driven plasmacytic differentiation in a large cohort of patients treated with bortezomib. RNA expression of three genes involved in PCs differentiation was investigated in purified PCs (CD138 + BM fraction) of well-characterized patients with newly diagnosed MM. One hundred and fifty-one patients enrolled in two multicenter clinical trials (the PAD-MEL100-LP-L and the VMP-VMPT) were assessed. 7,8 PCs were purified using anti-CD138-coated magnetic MicroBeads and AutoMACS Pro Separator (Miltenyi Biotech GmbH, Germany) following manufacturer specifications. Gene expression was investigated on isolated PCs with more than 90% of purity assessed by flow cytometry. RNA was extracted using the DNA/RNA Purification Kit (Norgen, Thorold, Canada). Complementary DNA was produced using High capacity cDNA RT Kit (Applied Biosytem, Foster Ciy, CA, USA). Quantitative PCR to measure RNA expression of XBP1, IRF4 and BLIMP1 was performed with the Abi Prism 7900HT (Applied Biosystems, Carlsbad, CA, USA) using a relative quantification based on Ct approach and GUSB (b-glucuronidase) as housekeeping gene. All RNA determinations were performed using the following assays: Hs00231936_m1 (XBP1), Hs01056533_m1 (IRF4), Hs00153357_m1 (BLIMP1). Patients were divided accord-
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 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 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".