Targeting PRMT5-Mediated DNA Repair Pathway in Extra-Nodal NK/T-Cell Lymphoma (ENKTL)
Bibliographic record
Abstract
Extra-Nodal (NK)/T-cell Lymphoma (ENKTL) is the most common subtype of NK lymphoma derived from EBV-infected NK cells. ENKTL is incurable and the 5-year survival is around 40% (<10% if disseminated) highlighting the unmet need for novel therapies. It has been shown that upregulation of DNA damage repair (DDR) plays a pivotal role in ENKTL survival by promoting genomic stability and resistance to lymphoma conventional DNA damaging therapies as reflected by the limited response rate (<50%). We identified protein arginine methyltransferase (PRMT5) to be oncogenic in many malignancies by supporting the cell cycle, WNT, and PI3K/AKT pathways. PRMT5, also promotes DDR through RNA splicing of TIP60/KAT5 and stabilization of 53BP1, essential for homologous recombination (HR) and non-homologous end joining (NHEJ), respectively. PRMT5-deficiency leads to DNA damage accumulation, cell cycle arrest, and apoptosis. Unbiased analysis of our RNA-seq data on ENKTL patient samples (n=22) show significant upregulation of DDR genes compared to normal NK cells. Interestingly, we also detected PRMT5 overexpression in 95% of this ENKTL cohort by RNA-seq, suggesting that PRMT5 may also be playing a role in the DDR within ENKTL. We confirmed these RNA-seq data and detected PRMT5 overexpression in primary ENKTL patients' samples (n=10) by immunohistochemical (IHC) staining compared to normal tonsils (n=5), in ENKTL-cell lines (NKL, NK92, and YT) and in a patient-derived xenograft (PDX) mouse model of ENKTL (ENKTL1) by western-blot. We hypothesize that PRMT5 inhibition 1) targets DNA repair in ENKTL cells leading to increased DNA damage-induced cell death and 2) sensitizes ENKTL cells to other DNA damage-inducing agents used in the current treatment of ENKTL leading to substantial increases in DNA damage-mediated cell death with combination therapy. To address this hypothesis, we used selective PRMT5-inhibitors, PRT382 and PRT808 (Prelude-Therapeutics) and detected cytotoxicity (IC50 25 - 500nM) in ENKTL-cell lines and ENKTL1. Furthermore, PRT382 significantly prolonged overall survival (OS) in our in vivo PDX mouse model of ENKTL1 (median OS: control 43 days vs PRT382 65 days; p=0.0088). Mechanistically, accumulation of DNA-damage was evident by the increase in phosphorylated forms of 1) H2AX (H2A histone family member X) at Ser139, and 2) Chk1/Chk2 (major DNA check points control) at Ser317/Ser345 and Thr68, respectively, in PRT808-treated cells and upon PRMT5 knock-down. Lastly, PRT808 sensitized NK-lymphoma cells to killing by doxorubicin (DNA-damage agent) and Olaparib (PARP1/2-inhibitor, key regulator of HR). In conclusion, PRMT5-inhibition results in an unrepairable level of DNA damage/subsequent apoptosis and sensitizes NK-lymphoma to other DNA damage-inducing agents. All together, these data justify targeting PRMT5 in ENKTL, as a single agent and in combination with other DNA damage agents which are an essential part of the current ENKTL regimen (Doxorubicin and Etoposide) representing a novel approach for better outcome. Further mechanistic studies investigating the role of PRMT5 in DNA repair and DNA damage in ENKTL cells are ongoing.
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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) | 0.000 | 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) | 0.000 | 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".