P-TEFb-dependent pathways in cancer
Bibliographic record
Abstract
Transcriptional regulators that play crucial roles in cancer progression have gained prominence as anticancer drug targets.Inhibitors of positive transcription elongation factor b (P-TEFb), a factor essential for promoter proximal pause release, have proven effective against a number of cancer types, including mixed lineage leukemia driven by translocations of the histone methyltransferase MLL.These translocations result in chimeric proteins that have been implicated in P-TEFb recruitment to target cancer-driving genes.P-TEFb is a kinase with multiple targets, including RNA polymerase II as well as two factors associated with the paused polymerase, negative elongation factor (NELF) and DRB sensitivity-inducing factor (DSIF).To determine the functional significance of P-TEFb-dependent pathways and elucidate the mechanisms underlying sensitivity to P-TEFb inhibitors in MLL-rearrangement associated leukemias, I characterized the responses to transcriptional inhibitor treatment of two cancer cell lines, THP-1, which has a MLL-rearrangement, and K562, which has unaltered MLL.I found that THP-1 exhibits reduced viability and greater loss of P-TEFb activity upon inhibition of P-TEFb.While consistent with the idea that MLL-rearrangement associated leukemias have increased dependency on P-TEFb, this work also raises the possibility that MLL-fusion proteins might globally impair P-TEFb, contrary to current models.I also took steps towards creating cell lines with phosphoacceptor site mutations in the P-TEFb target Spt5 using CRISPR/Cas9.My efforts revealed that double-stranded repair templates, which are commonly used in CRISPR/Cas9-mediated gene replacement, are non-specifically inserted into the genome at a high frequency.Overall, this work advances our understanding of the importance of P-TEFb-dependent pathways in cancer biology.iii Rsum Les rgulateurs de la transcription jouent un rle crucial dans la progression du cancer et sont, par consquent, devenus des cibles de mdicaments anticancreux intressantes.Les inhibiteurs du facteur positif d'longation de la transcription (P-TEFb), un facteur essentiel pour la sortie de la pause proximale au promoteur, se sont rvls efficaces contre plusieurs types de cancers, incluant la leucmie aigu de phnotype mixte entrane par des translocations de la mthyltransfrase MLL.Ces translocations forment des protines chimriques qui sont impliques dans le recrutement de P-TEFb aux gnes affectant ce cancer.P-TEFb est une kinase avec plusieurs cibles, incluant l'ARN polymrase II et deux facteurs associs la polymrase en pause, soit le facteur ngatif d'longation (NELF) et le facteur inductible la sensibilit au DRB (DSIF).Pour dterminer l'importance fonctionnelle des mcanismes rguls par P-TEFb et lucider les mcanismes sous-jacents la sensibilit aux inhibiteurs de P-TEFb dans les leucmies avec rarrangement de MLL, j'ai caractris les rponses aux inhibiteurs transcriptionnels de deux lignes cellulaires cancreuses, soit THP-1, qui possde un rarrangement de MLL, et K562, qui ne possde pas de rarrangement.J'ai dcouvert que THP-1 prsente une viabilit rduite et une perte plus importante de l'activit de P-TEFb lors de traitement avec les inhibiteurs de P-TEFb.Bien qu'ils conforment l'ide que les leucmies avec rarrangement de MLL dpendent davantage sur le P-TEFb, mes rsultats soulvent galement la possibilit que les protines de fusion MLL pourraient globalement altrer P-TEFb, contrairement aux modles actuels.J'ai aussi tent de crer des lignes cellulaires avec des mutations aux sites phosphoaccepteurs de Spt5, une cible de P-TEFb, en utilisant la technique CRISPR/Cas9.Mes efforts ont rvl que les molcules d'ADN double brin, qui sont couramment utiliss comme modles de rparation lors de l'essai CRISPR/Cas9, sont insrs dans le gnome de manire non-spcifique une frquence leve.Pris ensemble, mes rsultats amliorent notre comprhension de l'importance des mcanismes rguls par P-TEFb dans la biologie du cancer.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.005 |
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; both teacher heads agree on what is shown here.
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".