Functional synergism between IGF-IR tyrosine kinase and NPM-ALK oncogene identifies a novel role of IGF-IR in malignant lymphoma.
Bibliographic record
Abstract
C89 Deregulated IGF-IR signaling induces significant pathogenetic effects in a variety of human epithelial carcinomas including those of the breast, prostate, ovary, and lung. Despite that it promotes the growth of stimulated hematopoietic cells; a specific role of IGF-IR in lymphoid malignancies has not been identified. The full-length anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase of the insulin receptor superfamily. In humans, physiologic expression of ALK is restricted to embryonic cells of neural origin. A subset of T-cell lymphoma, identified according to the WHO classification scheme as ALK+ anaplastic large-cell lymphoma, harbors the t(2;5)(p23;q35), which involves ALK and NPM genes. This translocation generates the chimeric protein NPM-ALK that possesses constitutively active ALK. NPM-ALK-expressing T-cell lymphoma is an aggressive type of malignant lymphoma with a tendency to affect children and young adults. Despite initial response to current therapeutic modalities, 30% - 40% of the patients relapse and some eventually succumb. In the present study, we explored a role of IGF-IR in NPM-ALK-expressing T-cell lymphoma. Our results demonstrate that IGF-IR and its ligand IGF-I are widely expressed in NPM-ALK-expressing lymphoma cell lines and primary tumors. In addition, several of these cell lines release IGF-I in an autocrine fashion. We also identified novel functional collaborations between IGF-IR and NPM-ALK by which the 2 molecules reciprocally interact to maintain their phosphorylation status. In further support of the role of IGF-IR, IGF-I enhanced the viability of serum-deprived NPM-ALK-expressing T-cell lymphoma cell lines and salvaged these cells from apoptotic death. Selective targeting of IGF-IR induced concentration- and time-dependent apoptotic cell death and cell cycle arrest, and decreased proliferation and colony formation of NPM-ALK-expressing T-cell lymphoma cells. These effects were due to downregulation of pAKT, pSTAT3, Bcl-2, Bcl-XL, Mcl-1, and upregulation of p21. The negative effects of IGF-IR blockade on NPM-ALK-expressing T-cell lymphoma cells could also be attributed to the decrease or increase in the binding of the transcription modulators STAT3 or FKHR to DNA, respectively. Our results identify for the first time a novel and direct role of IGF-IR in any type of malignant lymphoma. In addition, these findings increase current knowledge of the biology of IGF-IR and NPM-ALK. Importantly, these findings carry significant therapeutic implications as they identify IGF-IR as a legitimate molecular target in NPM-ALK-expressing T-cell lymphoma, and probably in other types of malignant lymphoma in the future.
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 | 0.000 |
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".