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Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia.

ABSTRACT: Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.

SUBMITTER: Parker H

PROVIDER: S-EPMC5023049 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Downregulation of the histone methyltransferase SETD2 promotes imatinib resistance in chronic myeloid leukaemia cells.

Project description:ObjectivesEpigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR-ABL remain unclear.Materials and methodsThe level of SETD2 in imatinib-sensitive and imatinib-resistant chronic myeloid leukaemia (CML) cells was examined by immunoblotting and quantitative real-time PCR. We analysed CD34+ CD38- leukaemic stem cells by flow cytometry and colony formation assays upon SETD2 knockdown or overexpression. The impact of SETD2 expression alterations or small-molecule inhibitor JIB-04 targeting H3K36me3 loss on imatinib sensitivity was assessed by IC50, cell apoptosis and proliferation assays. Finally, RNA sequencing and ChIP-quantitative PCR were performed to verify putative downstream targets.ResultsSETD2 was found to act as a tumour suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukaemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell imatinib sensitivity and enhanced the chemotherapeutic effect.ConclusionsOur study not only emphasizes the regulatory mechanism of SETD2 in CML, but also provides promising therapeutic strategies for overcoming the imatinib resistance in patients with CML.

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Maintenance therapy for chronic lymphocytic leukaemia

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| S-EPMC6848968 | biostudies-literature

Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics during transcription.

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| S-EPMC8141928 | biostudies-literature

The histone methyltransferase Setd2 is indispensable for V(D)J recombination.

Project description:The diverse repertoire of T cell receptors (TCR) and immunoglobulins is generated through the somatic rearrangement of respective V, D and J gene segments, termed V(D)J recombination, during early T or B cell development. However, epigenetic regulation of V(D)J recombination is still not fully understood. Here we show that the deficiency of Setd2, a histone methyltransferase that catalyzes lysine 36 trimethylation on histone 3 (H3K36me3) in mice, causes a severe developmental block of thymocytes at the CD4-CD8- DN3 stage. While H3K36me3 is normally enriched at the TCRβ locus, Setd2 deficiency reduces TCRβ H3K36me3 and suppresses TCRβ V(D)J rearrangement by impairing RAG1 binding to TCRβ loci and the DNA double-strand break repair. Similarly, Setd2 ablation also impairs immunoglobulin V(D)J rearrangement to induce B cell development block at the pro-B stage. Lastly, SETD2 is frequently mutated in patients with primary immunodeficiency. Our study thus demonstrates that Setd2 is required for optimal V(D)J recombination and normal lymphocyte development.

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Project description:BackgroundGenomic information could help to reduce the morbidity effects of inappropriate treatment decisions in many disease areas, in particular cancer. However, evidence of the benefits that patients derive from genomic testing is limited. This study evaluated patient preferences for genomic testing in the context of chronic lymphocytic leukaemia (CLL).MethodsWe used a discrete choice experiment (DCE) survey to assess the preferences of CLL patients in the UK for genomic testing. The survey presented patients with 16 questions in which they had to choose between two possible test scenarios. Tests in these scenarios were specified in terms of six attributes, including test effectiveness, test reliability and time to receive results.Results219 patients completed the survey (response rate 20 %). Both clinical and process-related attributes were valued by respondents. Patients were willing to pay £24 for a 1 % increase in chemotherapy non-responders identified, and £27 to reduce time to receive test results by 1 day. Patients were also willing to wait an extra 29 days for test results if an additional one-third of chemotherapy non-responders could be identified, and would tolerate a genomic test being wrong 8 % of the time to receive this information.ConclusionCLL patients value the information that could be provided by genomic tests, and prefer combinations of test characteristics that more closely reflect future genomic testing practice than current genetic testing practice. Commissioners will need to carefully consider how genomic testing is operationalised in this context if the benefits of testing are to be realised.

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