Inhibition of the TPL2-MKK1/2-ERK1/2 pathway has cytostatic effect on B-Cell Lymphoma
Bibliographic record
Abstract
1) Abstract Diffuse Large B-Cell Lymphoma (DLBCL) are the most common form of non-Hodgkin lymphoma. Their molecular origin is heterogeneous and therefore treatments aimed at DLBCL must be adapted in function of the underlying molecular mechanisms driving cellular transformation. Constitutive activation of the protein kinases ERK1/2 is a hallmark of many B-cell malignancies. ERK1/2 activation which can occur downstream of the classical MAPK cascade via RAF or, in response to TLR stimulation, via the Tumor Promoting Locus 2 (TPL2) protein kinase. This pathway also relays signals from the MYD88 oncogenic mutant L265P, frequently found in hematologic malignancies. We report here that TPL2 participate to ERK1/2 activation downstream of BCR in a DLBCL cell line (OCI-Ly2). Moreover, we showed that a ERK2[Y316F] mutant increased c-Myc -luciferase reporter expression. We then investigated the impact of ERK1/2 inhibition on the proliferation of OCI-Ly2 cells. We found that blocking ERK1/2 MAPK signaling cascade using either MKK1/2 inhibitors (PD184352 and MEK162) or TPL2 inhibitor (Compound 1) was mainly cytostatic. Finally, we showed that while TPL2-MKK1/2 inhibition leads to cytostatic effect, Compound 1 has cytocidal effect at high concentrations, that is mediated via additional targets. Taken together, this study demonstrates the involvement of TPL2 in oncogenic signaling of DLBCL and supports the idea that combination therapy targeting multiple molecular pathways linked to cellular transformation is a superior avenue for future therapies.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".