Restoring chromatin accessibility for MLL reactivates latent tumor suppression-mediated vulnerability to proteasome inhibitors.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA574987 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10203761.fastq.gz | Fastqsanger.gz | |||
| SRR10203762.fastq.gz | Fastqsanger.gz | |||
| SRR10203763.fastq.gz | Fastqsanger.gz | |||
| SRR10203764.fastq.gz | Fastqsanger.gz | |||
| SRR10203765.fastq.gz | Fastqsanger.gz |
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Project description:MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor suppressive activity which can be exploited as effective cancer treatment strategies using pharmacological means such as proteasome inhibitors (PIs). Here, we show that wild-type MLL is indispensable for the latent tumor suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accessibility and subsequent degradation of MLL, compromises the latent tumor suppressive activity of MLL fusions and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming and can be specifically restored by histone deacetylase (HDAC) inhibitors.
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Project description:MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor-suppressive activity, which can be exploited as effective cancer treatment strategies using pharmacological means such as proteasome inhibitors (PIs). Here, using MLL-rearranged xenografts and MLL leukemic cells as models, we show that wild-type MLL is indispensable for the latent tumor-suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accumulation and subsequent degradation of MLL, compromises the latent tumor suppression of MLL-AF4 and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming through the H2Bub-ASH2L-MLL axis and can be specifically restored by histone deacetylase (HDAC) inhibitors, which induce histone acetylation and recruits MLL on chromatin to promote cell cycle gene expression. Our findings not only demonstrate the mechanism underlying the inevitable acquisition of PI resistance in MLL leukemic cells, but also illustrate that preventing the emergence of PI-resistant cells constitutes a novel rationale for combination therapy with PIs and HDAC inhibitors in MLL leukemias.
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Project description:Chromosomal translocations disrupting MLL generate MLL-fusion proteins that induce aggressive leukemias. Unexpectedly, MLL-fusion proteins are rarely observed at high levels, suggesting excessive MLL-fusions may be incompatible with a malignant phenotype. Here, we used clinical proteasome inhibitors, bortezomib and carfilzomib, to reduce the turnover of endogenous MLL-fusions and discovered that accumulated MLL-fusions induce latent, context-dependent tumor suppression programs. Specifically, in MLL pro-B lymphoid, but not myeloid, leukemias, proteasome inhibition triggers apoptosis and cell cycle arrest involving activation cleavage of BID by caspase-8 and upregulation of p27, respectively. Furthermore, proteasome inhibition conferred preliminary benefit to patients with MLL-AF4 leukemia. Hence, feasible strategies to treat cancer-type and oncogene-specific cancers can be improvised through harnessing inherent tumor suppression properties of individual oncogenic fusions.
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Project description:We found that GSCs were highly sensitive to proteasome inhibition due to an underlying dependency on an increased protein synthesis rate, and loss of autophagy, associated with PTEN loss and activation of the PI3K/mTOR pathway. In contrast, combinatory inhibition of autophagy and the proteasome, resulted in enhanced cytotoxicity specifically in GSCs that did express PTEN. Finally, proteasome inhibition specifically increased cell death markers in 3D glioblastoma organoids, suppressed tumor growth, and increased survival of mice orthotopically engrafted with GSCs. As perturbations of the PI3K/mTOR pathway occur in nearly 50% of GBMs, these findings suggest that a significant fraction of these tumors could be vulnerable to proteasome inhibition.
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Project description:The interplay between cancer cells and microenvironment can influence treatment response and plays a key role in the emergence of drug resistance. Rapidly acquired resistance prevents proteasome inhibitors (PIs) therapies from achieving stable and complete responses. Investigating the underlying mechanisms and developing effective strategies against PI resistance are highly desired in the clinic. Here we uncovered that PI resistance was reversible in MLL leukemia, which consistent with the finding that patients could regain sensitivity to PIs after a drug holiday. Exosomes derived from drug-tolerant cells could transmit PI resistance to sensitive cells via facilitating cell cycle arrest and stemness pathway in MLL leukemia cells. Furthermore, TieDIE algorithm integration analysis of transcriptome and proteome datasets identified candidate exosomal proteins, providing potential therapeutic targets for treating refractory MLL leukemia. Therefore, exosomal regulatory proteins may serve as a predictor and a potential therapeutic target for PI resistance, and inhibiting the secretion of exosomes is a promising strategy for restoring PI resistance in vivo, which provides a paradigm and may also be applied for the treatment of other cancers resulting from chemotherapy relapse.
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