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The Capital Region of Denmark - a part of Copenhagen University Hospital
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H3K9 dimethylation safeguards cancer cells against activation of the Interferon pathway

Research output: Book/ReportPh.D. thesis

  1. H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway

    Research output: Contribution to journalJournal articlepeer-review

  2. The ASXL1-G643W variant accelerates the development of CEBPA mutant acute myeloid leukemia

    Research output: Contribution to journalJournal articlepeer-review

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Summary
Acute myeloid leukemia (AML) is an aggressive blood cancer of the myeloid lineage, which is defined as an abnormal clonal expansion of undifferentiated cells in the bone marrow. The incidence of AML
strongly correlates with population aging due to an accumulation of mutations in the immature blood cells. The current treatment for adult AML is based on conventional chemotherapy and the prognosis is fairly good in patients under the age of 60. However, the outcome for elderly patients remains very poor as a result of treatment toxicity and relapse. Low-intensity therapies such as hypomethylating agents have been implemented, which have improved the short-term survival but sadly not the longterm outlook for these patients. Therefore, a need to improve survival and the treatment regime in the majority of AML patients remains.
Our understanding of the pathophysiology in AML is constantly increasing and it has been groundbreaking in the discovery of new therapies. In this study, we demonstrate a novel mechanism of the H3K9me3 histone methyltransferase (HMT) SUV39H1 in AML and find that depletion of the
protein leads to a slower progression of AML in vivo. Moreover, we demonstrate a significant effect of SUV39H1 depletion on proliferation, differentiation, and apoptosis in several human AML cell lines.
The observed phenotype is dependent on induction of the interferon (IFN) pathway, which is known to restrict cancer cells through antineoplastic and immune-modulatory effects. Mechanistically, we show that loss of SUV39H1 results in destabilization of the H3K9me2 HMTs, G9A, and GLP, and subsequently a global decrease in H3K9me2. Silencing of IFN genes is mainly carried out through the H3K9me2 mark and indeed we were able to mimic the phenotype of SUV39H1 depletion by inhibiting the enzymatic activity of G9A and GLP. Furthermore, we observe a synergistic effect by targeting both
H3K9me2 and DNA methylation, likely through re-expression of retrotransposons which are potent triggers of the IFN pathway. Finally, we uncover SUV39H1 as a potential biomarker in AML patients treated with hypomethylating agents. In summary, we identify a potential target for the future treatment of AML and a prognostic relevant role for SUV39H1 and H3K9me2 in these patients.
Original languageEnglish
PublisherEget Forlag
Number of pages121
Publication statusPublished - 14 Sep 2021

ID: 78938793