Abstract RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N 6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets. 

Methyltransferase-like proteins in cancer biology and potential therapeutic targeting

Survival in Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disease following haematopoietic stem-cell transplant (HSCT) or solid organ transplant (SOT) is poor after failure of initial therapy, indicating an urgent need for therapies for this ultra-rare disease. With recent EU marketing authorisation, tabelecleucel is the first off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy to receive approval for treatment of relapsed or refractory EBV-positive post-transplant lymphoproliferative disease. We aimed to determine the clinical benefit of tabelecleucel in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease following HSCT or SOT.In this global, multicentre, open-label, phase 3 trial, eligible patients (of any age) had biopsy-proven EBV-positive post-transplant lymphoproliferative disease, disease that was relapsed or refractory to rituximab after HSCT and rituximab with or without chemotherapy after SOT, and partially HLA-matched and appropriately HLA-restricted tabelecleucel available. Patients received tabelecleucel administered intravenously at 2 × 106 cells per kg on days 1, 8, and 15 in 35-day cycles and are assessed for up to 5 years for survival post-treatment initiation. The primary endpoint was objective response rate. All patients who received at least one dose of tabelecleucel were included in safety and efficacy analyses. This trial is registered with ClinicalTrials.gov, NCT03394365, and is ongoing.From June 27, 2018, to Nov 5, 2021, 63 patients were enrolled, of whom 43 (24 [56%] male and 19 [44%] female) were included, 14 had prior HSCT, 29 had SOT. Seven (50%, 95% CI 23-77) of 14 participants in the HSCT group and 15 (52%, 33-71) of 29 participants in the SOT group had an objective response, with a median follow-up of 14·1 months (IQR 5·7-23·9) and 6·0 months (1·8-18·4), respectively. The most common grade 3 or 4 treatment-emergent adverse events were disease progression (in four [29%] of 14 in HSCT and eight [28%] of 29 in SOT) and decreased neutrophil count (in four [29%] of 14 in HSCT and four [14%] of 29 in SOT). Treatment-emergent serious adverse events were reported in 23 (53%) of 43 patients and fatal treatment-emergent adverse events in five (12%); no fatal treatment-emergent adverse event was treatment-related. There were no reports of tumour flare reaction, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, transmission of infectious diseases, marrow rejection, or infusion reactions. No events of graft-versus-host disease or SOT rejection were reported as related to tabelecleucel.Tabelecleucel provides clinical benefit in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease, for whom there are no other approved therapies, without evidence of safety concerns seen with other adoptive T-cell therapies. These data represent a potentially transformative and accessible treatment advance for patients with relapsed or refractory disease with few treatment options.Atara Biotherapeutics. 

Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial.

Internal N6-methyladenosine (m6A) modifications are among the most abundant modifications of messenger RNA, playing a critical role in diverse biological and pathological processes. However, the functional role and regulatory mechanism of m6A modifications in the immune response to Mycobacterium tuberculosis infection remains unknown. Here, we report that methyltransferase-like 14 (METTL14)-dependent m6A methylation of NAPDH oxidase 2 (Nox2) mRNA was crucial for the host immune defense against M. tuberculosis infection and that M. tuberculosis-secreted antigen EsxB (Rv3874) inhibited METTL14-dependent m6A methylation of Nox2 mRNA. Mechanistically, EsxB interacted with p38 MAP kinase and disrupted the association of TAB1 with p38, thus inhibiting the TAB1-mediated autophosphorylation of p38. Interaction of EsxB with p38 also impeded the binding of p38 with METTL14, thereby inhibiting the p38-mediated phosphorylation of METTL14 at Thr72. Inhibition of p38 by EsxB restrained liquid-liquid phase separation (LLPS) of METTL14 and its subsequent interaction with METTL3, preventing the m6A modification of Nox2 mRNA and its association with the m6A-binding protein IGF2BP1 to destabilize Nox2 mRNA, reduce ROS levels, and increase intracellular survival of M. tuberculosis. Moreover, deletion or mutation of the phosphorylation site on METTL14 impaired the inhibition of ROS level by EsxB and increased bacterial burden or histological damage in the lungs during infection in mice. These findings identify a previously unknown mechanism that M. tuberculosis employs to suppress host immunity, providing insights that may empower the development of effective immunomodulators that target M. tuberculosis. 

Mycobacterium tuberculosis inhibits METTL14-mediated m6A methylation of Nox2 mRNA and suppresses anti-TB immunity

Epigenetic modifications play critical roles during somatic cell nuclear transfer (SCNT) embryo development. Whether RNA N6-methyladenosine (m6 A) affects the developmental competency of SCNT embryos remains unclear. Here, we showed that porcine bone marrow mesenchymal stem cells (pBMSCs) presented higher RNA m6 A levels than those of porcine embryonic fibroblasts (pEFs). SCNT embryos derived from pBMSCs had higher RNA m6 A levels, cleavage, and blastocyst rates than those from pEFs. Compared with pEFs, the promoter region of METTL14 presented a hypomethylation status in pBMSCs. Mechanistically, DNA methylation regulated METTL14 expression by affecting the accessibility of transcription factor SP1 binding, highlighting the role of the DNA methylation/SP1/METTL14 pathway in donor cells. Inhibiting the DNA methylation level in donor cells increased the RNA m6 A level and improved the development efficiency of SCNT embryos. Overexpression of METTL14 significantly increased the RNA m6 A level in donor cells and the development efficiency of SCNT embryos, whereas knockdown of METTL14 suggested the opposite result. Moreover, we revealed that RNA m6 A-regulated TOP2B mRNA stability, translation level, and DNA damage during SCNT embryo development. Collectively, our results highlight the crosstalk between RNA m6 A and DNA methylation, and the crucial role of RNA m6 A during nuclear reprogramming in SCNT embryo development.

DNA methylation regulates RNA m6 A modification through transcription factor SP1 during the development of porcine somatic cell nuclear transfer embryos.

Increased N6-methyladenosine is related to the promotion of the methyltransferase METTL14 in ovarian aging

The METTL3-METTL14 complex, the "writer" of N6-methyladenosine (m6A), plays an important role in many biological processes. Previous studies have shown that Mettl3 overexpression can increase the level of m6A and promote somatic cell reprogramming. Here, we demonstrate that Mettl14, another component of the methyltransferase complex, can significantly enhance the generation of induced pluripotent stem cells (iPSCs) in an m6A-independent manner. In cooperation with Oct4, Sox2, Klf4, and c-Myc, overexpressed Mettl14 transiently promoted senescence-associated secretory phenotype (SASP) gene expression in non-reprogrammed cells in the late stage of reprogramming. Subsequently, we demonstrated that interleukin-6 (IL-6), a component of the SASP, significantly enhanced somatic cell reprogramming. In contrast, blocking the SASP using a senolytic agent or a nuclear factor κB (NF-κB) inhibitor impaired the effect of Mettl14 on reprogramming. Our results highlight the m6A-independent function of Mettl14 in reprogramming and provide new insight into the interplay between senescence and reprogramming in vitro. 

http://www.cell.com/article/S2213671122003708/pdf

Mettl14-driven senescence-associated secretory phenotype facilitates somatic cell reprogramming

Background: Tabelecleucel is an investigational, off-the-shelf, allogeneic Epstein–Barr Virus (EBV)-specific T-cell immunotherapy being explored in patients (pts) with EBV-driven post-transplant lymphoproliferative disease (EBV+ PTLD). Median overall survival (OS) after rituximab (R) ± chemotherapy (C) failure is 0.7 months in EBV+ PTLD post allogeneic hematopoietic cell transplant (HCT) (Sanz ASH 2021) and 4.1 months post solid organ transplant (SOT) after R+C failure (Dharnidharka ASH 2021), demonstrating an urgent need for therapies in this ultra-rare disease. Tabelecleucel has shown promising outcomes (Prockop JCI 2020). Additionally, an investigator-assessed objective response rate (ORR) of >60% with >80% 2-year OS (Prockop EBMT 2021, Prockop ATC 2021, Prockop ASH 2021) was seen in pts with relapsed/refractory (R/R) EBV+ PTLD, with either complete or partial response to tabelecleucel. Safety data in >180 pts with tabelecleucel treated EBV+ PTLD demonstrate tumor flare reaction (TFR) as the only identified risk (Atara Biotherapeutics, Data on file). Aims: Report data from the ongoing Phase 3 ALLELE study (NCT03394365). Methods: ALLELE is a multicenter, open-label study investigating tabelecleucel in pts with EBV+ PTLD post HCT after R failure (n=33) and post SOT after R±C failure (n=33). Pts receive tabelecleucel at 2 x 106 cells/kg on Days 1, 8 and 15 in 35-day cycles. Response is evaluated by investigator and by independent oncologic response adjudication (IORA; primary assessment) using Lugano Classification with LYRIC modification. Efficacy endpoints include ORR, duration of response (DOR), time to response (TTR), and OS. Pts are assessed post treatment for up to 5 years for survival. Results: As of May 2021, 38 pts (14 HCT, 24 SOT) were evaluable by IORA and had the opportunity for 6 months follow-up. Median age was 52.9 (range, 3.2–81.5) years, 44.4%/47.2% of pts were high/intermediate risk per PTLD-adapted prognostic index, and median number of lines of prior systemic treatment was 1 (range, 1–5). R/R HCT and SOT pts received a median (range) of 3 (1–5) and 2 (1–6) cycles of tabelecleucel, respectively. ORR was 50.0% (19/38, 95% CI: 33.4, 66.6) overall, 50.0% (7/14, 95% CI: 23.0, 77.0) in HCT, and 50.0% (12/24, 95% CI: 29.1, 70.9) in SOT (Table). Overall, median TTR was 1.1 (0.7–4.7) months, 11 of 19 responders had DOR > 6 months, and median DOR was not reached (Table). Median OS was 18.4 (95% CI: 6.9, NR) months overall, not yet reached for HCT, and 16.4 (95% CI: 3.5, NR) months for SOT. 1-year survival rates were 61.1% (95% CI: 42.9, 75.0) overall, 66.8% (95% CI: 32.4, 86.6) for HCT, and 57.4% (95% CI: 35.2, 74.5) for SOT. Median OS was NR (95% CI: 16.4, NR) for responders and 5.7 (95% CI: 1.8, 12.1) months for non-responders. Responders had a higher 1-year survival rate vs non-responders: 89.2% (95% CI: 63.1, 97.2) vs 32.4% (95% CI: 12.1, 54.9) (Table). Serious treatment emergent AEs (TEAEs) and fatal TEAEs were reported in 57.1% and 7.1% of HCT and 62.5% and 16.7% of SOT pts respectively. No fatal TEAE was treatment related. There were no reports of TFR, infusion reactions, cytokine release syndrome, marrow rejection, or transmission of infectious diseases, and no events of graft vs host disease or organ rejection reported as related to tabelecleucel. Image:Summary/Conclusion: Tabelecleucel Phase 3 data show clinically meaningful outcomes and promising ORR and OS in a pt population with poor survival and no approved therapies. Tabelecleucel was well tolerated without evidence of safety concerns typically observed with other adoptive T-cell therapies. 

S256: tabelecleucel for ebv-driven post-transplant lymphoproliferative disease following allogeneic hematopoietic cell or solid organ transplant after failure of rituximab ± chemotherapy (allele)

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Mettl14-driven senescence-associated secretory phenotype facilitates somatic cell reprogramming

S256: tabelecleucel for ebv-driven post-transplant lymphoproliferative disease following allogeneic hematopoietic cell or solid organ transplant after failure of rituximab ± chemotherapy (allele)