Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Leukemia
2023 Dec 01;3712:2404-2413. doi: 10.1038/s41375-023-02052-2.
Show Gene links
Show Anatomy links
Mutations in the histone methyltransferase Ezh2 drive context-dependent leukemia in Xenopus tropicalis.
Tulkens D, Boelens M, Naert T, Carron M, Demuynck S, Dewaele S, Van Isterdael G, Creytens D, Pieters T, Goossens S, Van Vlierberghe P, Vleminckx K.
???displayArticle.abstract???
CRISPR-mediated simultaneous targeting of candidate tumor suppressor genes in Xenopus tropicalis allows fast functional assessment of co-driver genes for various solid tumors. Genotyping of tumors that emerge in the mosaic mutant animals rapidly exposes the gene mutations under positive selection for tumor establishment. However, applying this simple approach to the blood lineage has not been attempted. Multiple hematologic malignancies have mutations in EZH2, encoding the catalytic subunit of the Polycomb Repressive Complex 2. Interestingly, EZH2 can act as an oncogene or a tumor suppressor, depending on cellular context and disease stage. We show here that mosaic CRISPR/Cas9 mediated ezh2 disruption in the blood lineage resulted in early and penetrant acute myeloid leukemia (AML) induction. While animals were co-targeted with an sgRNA that induces notch1 gain-of-function mutations, sequencing of leukemias revealed positive selection towards biallelic ezh2 mutations regardless of notch1 mutational status. Co-targeting dnm2, recurrently mutated in T/ETP-ALL, induced a switch from myeloid towards acute T-cell leukemia. Both myeloid and T-cell leukemias engrafted in immunocompromised hosts. These data underline the potential of Xenopus tropicalis for modeling human leukemia, where mosaic gene disruption, combined with deep amplicon sequencing of the targeted genomic regions, can rapidly and efficiently expose co-operating driver gene mutations.
Basheer,
Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML.
2019, Pubmed
Basheer,
Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML.
2019,
Pubmed Boel,
BATCH-GE: Batch analysis of Next-Generation Sequencing data for genome editing assessment.
2016,
Pubmed
,
Xenbase Chang,
The role of EZH2 in tumour progression.
2012,
Pubmed Ciau-Uitz,
The embryonic origins and genetic programming of emerging haematopoietic stem cells.
2016,
Pubmed
,
Xenbase Comet,
Maintaining cell identity: PRC2-mediated regulation of transcription and cancer.
2016,
Pubmed Ernst,
Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders.
2010,
Pubmed Ge,
Novel dynamin 2 mutations in adult T-cell acute lymphoblastic leukemia.
2016,
Pubmed George,
Comprehensive genomic profiles of small cell lung cancer.
2015,
Pubmed Göllner,
Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia.
2017,
Pubmed Kelleher,
Respiratory distress secondary to pulmonary leukemia.
1981,
Pubmed Kim,
Targeting EZH2 in cancer.
2016,
Pubmed Liu,
The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia.
2017,
Pubmed Mann,
Analyzing tumor heterogeneity and driver genes in single myeloid leukemia cells with SBCapSeq.
2016,
Pubmed Maxham,
Hematologic reference intervals for Xenopus tropicalis with partial use of automatic counting methods and reliability of long-term stored samples.
2016,
Pubmed
,
Xenbase McDonald,
The opposing roles of Wnt-5a in cancer.
2009,
Pubmed
,
Xenbase Moreno-Mateos,
CRISPRscan: designing highly efficient sgRNAs for CRISPR-Cas9 targeting in vivo.
2015,
Pubmed
,
Xenbase Naert,
CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping.
2021,
Pubmed
,
Xenbase Naert,
RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma in Xenopus tropicalis.
2020,
Pubmed
,
Xenbase Naert,
CRISPR/Cas9 mediated knockout of rb1 and rbl1 leads to rapid and penetrant retinoblastoma development in Xenopus tropicalis.
2016,
Pubmed
,
Xenbase Neumann,
Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations.
2013,
Pubmed Nishioka,
BCR/ABL increases EZH2 levels which regulates XIAP expression via miRNA-219 in chronic myeloid leukemia cells.
2016,
Pubmed Ntziachristos,
Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia.
2014,
Pubmed O'Carroll,
The polycomb-group gene Ezh2 is required for early mouse development.
2001,
Pubmed Oliveira,
IL-7R-mediated signaling in T-cell acute lymphoblastic leukemia: An update.
2019,
Pubmed Potenza,
Leukaemic pulmonary infiltrates in adult acute myeloid leukaemia: a high-resolution computerized tomography study.
2003,
Pubmed Robert,
Comparative and developmental study of the immune system in Xenopus.
2009,
Pubmed
,
Xenbase Rogers,
Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis.
1986,
Pubmed Safaei,
Double sword role of EZH2 in leukemia.
2018,
Pubmed Sanchez-Martin,
The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia.
2017,
Pubmed Schäfer,
EZH2 mutations and promoter hypermethylation in childhood acute lymphoblastic leukemia.
2016,
Pubmed Shen,
Double agents: genes with both oncogenic and tumor-suppressor functions.
2018,
Pubmed Tremblay,
Loss-of-function mutations of Dynamin 2 promote T-ALL by enhancing IL-7 signalling.
2016,
Pubmed Tulkens,
Engraftment of Allotransplanted Tumor Cells in Adult rag2 Mutant Xenopus tropicalis.
2022,
Pubmed
,
Xenbase Van der Meulen,
The epigenetic landscape of T-cell acute lymphoblastic leukemia.
2014,
Pubmed Van Nieuwenhuysen,
TALEN-mediated apc mutation in Xenopus tropicalis phenocopies familial adenomatous polyposis.
2015,
Pubmed
,
Xenbase Van Vlierberghe,
Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia.
2013,
Pubmed Vardiman,
The World Health Organization (WHO) classification of the myeloid neoplasms.
2002,
Pubmed Xu,
Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring.
2011,
Pubmed Yap,
The opposing roles of NOTCH signalling in head and neck cancer: a mini review.
2015,
Pubmed Zhang,
The genetic basis of early T-cell precursor acute lymphoblastic leukaemia.
2012,
Pubmed
