ArticleOncogene2019
Inhibition of DOT1L and PRMT5 promote synergistic anti-tumor activity in a human MLL leukemia model induced by CRISPR/Cas9.
Article in Oncogene, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 37 citations in OpenAlex.
- Characterizing the impact of MLL fusion variants and fusion partners on leukemia plasticity using a human CRISPR-engineered MLL-rearranged leukemia model.Neoplasia (New York, N.Y.) · 2026Article
- Review
- Cracking PRMT5: Mechanistic insights, clinical advances, and AI-driven strategies.Cancer letters · 2025Review
- Feasibility and Safety of Targeting Mitochondria Function and Metabolism in Acute Myeloid Leukemia.Current pharmacology reports · 2024Article
- Only InfantInternational journal of molecular sciences · 2024Article
- Three-dimensional chromatin landscapes in MLLr AML.Experimental hematology & oncology · 2024Article
- The RORɣ/SREBP2 pathway is a master regulator of cholesterol metabolism and serves as potential therapeutic target in t(4;11) leukemia.Oncogene · 2024Article
- Loss of SMAD1 in acute myeloid leukemia withFrontiers in oncology · 2024Article
- Uncovering NOTCH1 as a Promising Target in the Treatment ofInternational journal of molecular sciences · 2023Article
- Therapeutic vulnerabilities of cancer stem cells and effects of natural products.Natural product reports · 2023Review
- Targeting MYC in combination with epigenetic regulators induces synergistic anti-leukemic effects in MLLr leukemia and simultaneously improves immunity.Neoplasia (New York, N.Y.) · 2023Article
- Article
- Multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation.Scientific reports · 2023Article
- Creation of Philadelphia chromosome by CRISPR/Cas9-mediated double cleavages on BCR and ABL1 genes as a model for initial event in leukemogenesis.Cancer gene therapy · 2023Article
- Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies.Cancers · 2022Review
- A CRISPR view of hematopoietic stem cells: Moving innovative bioengineering into the clinic.American journal of hematology · 2022Review
- Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors in Oncology Clinical Trials: A review.Journal of immunotherapy and precision oncology · 2022Review
- Protein arginine methylation: from enigmatic functions to therapeutic targeting.Nature reviews. Drug discovery · 2021Review
- Integrative methylome-transcriptome analysis unravels cancer cell vulnerabilities in infant MLL-rearranged B cell acute lymphoblastic leukemia.The Journal of clinical investigation · 2021Article
- Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease.Nature reviews. Drug discovery · 2021Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
MLL rearrangements play a crucial role in leukemogenesis and comprise a poor prognosis. Therefore, new treatment strategies are urgently needed. We used the CRISPR/Cas9 system to generate an innovative leukemia model based on 100% pure MLL-AF4 or -AF9 rearranged cells derived from umbilical cord blood with indefinite growth in cell culture systems. Our model shared phenotypical, morphological and molecular features of patient cells faithfully mimicking the nature of the disease. Thus, it serves as a fundamental basis for pharmacological studies: inhibition of histone methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is one specific therapeutic approach currently tested in clinical trials. However, success was limited by restricted response warranting further investigation of drug combinations. Recently, it has been shown that the inhibition of protein arginine methyltransferase 5 (PRMT5) exhibits anti-tumoral activity against human cell lines and in MLL mouse models. Here, we used DOT1L and PRMT5 inhibitors in our human MLL-rearranged model demonstrating dose-dependent reduced proliferation, impairment of cell cycle, increasing differentiation, apoptosis, downregulation of target genes and sensitization to chemotherapy. Strikingly, the combination of both compounds led to synergistic anti-tumoral effects. Our study provides a strong rationale for novel targeted combination therapies to improve the outcome of MLL-rearranged leukemias.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.