Senescence Induced by BMI1 Inhibition is a Therapeutic Vulnerability in H3K27M-Mutant DIPG

Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using model systems of pediatric high-grade glioma, we show that rapid genome-wide reorganization of active chromatin facilitates PTEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of PTEFb disrupts this chromatin reorganization and blunts transcriptional induction, abrogating key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies.

show abstract

“…Cell lines and culture technique. HGG and normal cells were maintained as previously described 33,96 .…”

Section: Methodsmentioning

confidence: 99%

Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy

Walker

Sobral

Danis

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In response to radiation-induced DNA damage, LEDGF recruits CtBP, a protein required for resection of DSBs, to the damage site, facilitating HR repair [40] . Furthermore, expression of the E3 ubiquitin ligase BMI1, a core subunit of the polycomb repressive complex 1 (PRC1), is upregulated in DIPG [41] . Correspondingly, levels of monoubiquitinated histone H2A lysine 119 (H2A119ub), a product of BMI1, were higher in cells expressing H3K27M compared to those expressing wild-type histone H3 [ 41 , 34 ].…”

Section: Epigenetic Regulation Of Dna Double Strand Break Repair and ...mentioning

confidence: 99%

“…Furthermore, expression of the E3 ubiquitin ligase BMI1, a core subunit of the polycomb repressive complex 1 (PRC1), is upregulated in DIPG [41] . Correspondingly, levels of monoubiquitinated histone H2A lysine 119 (H2A119ub), a product of BMI1, were higher in cells expressing H3K27M compared to those expressing wild-type histone H3 [ 41 , 34 ]. Like LEDGF, BMI1 and H2AK119ub have been reported to facilitate CtIP recruitment and DNA end resection at DSBs [42] .…”

Section: Epigenetic Regulation Of Dna Double Strand Break Repair and ...mentioning

confidence: 99%

Developing H3K27M mutant selective radiosensitization strategies in diffuse intrinsic pontine glioma

et al. 2023

View full text Add to dashboard Cite

“…Furthermore, loss of one allele of p53 reduces H-RasV12 oncogene-induced senescence in an orthotopic GBM model, as evidenced by reduced SA-β-gal staining, and decreases mouse survival time 21 . Finally, a recent study revealed the dual effect of therapy-induced senescence (TIS) following BMI1 inhibitor treatment of diffuse intrinsic pontine glioma tumor (a pediatric high-grade glioma), which initially attenuates tumor cell self-renewal and growth, but later leads to SASP-mediated tumor recurrence 22 . This study confirmed the detrimental function of persistent senescent cells in glial tumors, and suggested that senescent cells could represent an actionable target to mitigate the process of gliomagenesis 6 .…”

Section: Introductionmentioning

confidence: 99%

Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma

Salam

Saliou

Bielle

et al. 2022

Preprint

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression. Senescent cells were identified in patient and mouse GBMs. Partial removal of p16Ink4a-expressing malignant senescent cells, which make up less than 7 % of the tumor, modified the tumor ecosystem and improved the survival of GBM-bearing mice. By combining single cell and bulk RNA sequencing, immunohistochemistry and genetic knockdowns, we identified the NRF2 transcription factor as a determinant of the senescent phenotype. Remarkably, our mouse senescent transcriptional signature and underlying mechanisms of senescence are conserved in patient GBMs, in whom higher senescence scores correlate with shorter survival times. These findings suggest that senolytic drug therapy may be a beneficial adjuvant therapy for patients with GBM.

show abstract

Senescence Induced by BMI1 Inhibition is a Therapeutic Vulnerability in H3K27M-Mutant DIPG

Cited by 5 publications

References 38 publications

Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy

Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy

Developing H3K27M mutant selective radiosensitization strategies in diffuse intrinsic pontine glioma

Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma

Contact Info

Product

Resources

About