DAPK3 participates in the mRNA processing of immediate early genes in chronic lymphocytic leukaemia
Cross‐linking of the B‐cell receptor (BCR) induces transcriptional activation of immediate early genes (IEGs) including EGR1 and DUSP2 in chronic lymphocytic leukaemia (CLL). Here, we have shown that this transcriptional activation correlated with histone H3 threonine 6 and 11 phosphorylation. Both...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-06-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12692 |
| _version_ | 1811206886315261952 |
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| author | Fraser Thomas Katie B. Holmes Sarah Kreuz Peter Hillmen Pascal F. Lefevre |
| author_facet | Fraser Thomas Katie B. Holmes Sarah Kreuz Peter Hillmen Pascal F. Lefevre |
| author_sort | Fraser Thomas |
| collection | DOAJ |
| description | Cross‐linking of the B‐cell receptor (BCR) induces transcriptional activation of immediate early genes (IEGs) including EGR1 and DUSP2 in chronic lymphocytic leukaemia (CLL). Here, we have shown that this transcriptional activation correlated with histone H3 threonine 6 and 11 phosphorylation. Both transcription and histone post‐translational modifications are repressed by ibrutinib, a small molecule inhibitor used in CLL treatment. Moreover, we have identified the death‐associated protein kinase 3 (DAPK3), as the kinase mediating these histone phosphorylation marks in response to activation of the BCR signalling pathway with this kinase being recruited to RNA polymerase II in an anti‐IgM‐dependent manner. DAPK inhibition mimics ibrutinib‐induced repression of both IEG mRNA and histone H3 phosphorylation and has anti‐proliferative effect comparable to ibrutinib in CLL in vitro. DAPK inhibitor does not repress transcription itself but impacts on mRNA processing and has a broader anti‐tumour effect than ibrutinib, by repressing both anti‐IgM‐ and CD40L‐dependent activation. |
| first_indexed | 2024-04-12T03:55:28Z |
| format | Article |
| id | doaj.art-e1a16b42b1b04727afc2b91d8753eff2 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-12T03:55:28Z |
| publishDate | 2020-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-e1a16b42b1b04727afc2b91d8753eff22022-12-22T03:48:52ZengWileyMolecular Oncology1574-78911878-02612020-06-011461268128110.1002/1878-0261.12692DAPK3 participates in the mRNA processing of immediate early genes in chronic lymphocytic leukaemiaFraser Thomas0Katie B. Holmes1Sarah Kreuz2Peter Hillmen3Pascal F. Lefevre4Division of Haematology and Immunology Leeds Institute of Medical Research at St. James's University of Leeds UKDivision of Haematology and Immunology Leeds Institute of Medical Research at St. James's University of Leeds UKDivision of Haematology and Immunology Leeds Institute of Medical Research at St. James's University of Leeds UKDivision of Haematology and Immunology Leeds Institute of Medical Research at St. James's University of Leeds UKDivision of Haematology and Immunology Leeds Institute of Medical Research at St. James's University of Leeds UKCross‐linking of the B‐cell receptor (BCR) induces transcriptional activation of immediate early genes (IEGs) including EGR1 and DUSP2 in chronic lymphocytic leukaemia (CLL). Here, we have shown that this transcriptional activation correlated with histone H3 threonine 6 and 11 phosphorylation. Both transcription and histone post‐translational modifications are repressed by ibrutinib, a small molecule inhibitor used in CLL treatment. Moreover, we have identified the death‐associated protein kinase 3 (DAPK3), as the kinase mediating these histone phosphorylation marks in response to activation of the BCR signalling pathway with this kinase being recruited to RNA polymerase II in an anti‐IgM‐dependent manner. DAPK inhibition mimics ibrutinib‐induced repression of both IEG mRNA and histone H3 phosphorylation and has anti‐proliferative effect comparable to ibrutinib in CLL in vitro. DAPK inhibitor does not repress transcription itself but impacts on mRNA processing and has a broader anti‐tumour effect than ibrutinib, by repressing both anti‐IgM‐ and CD40L‐dependent activation.https://doi.org/10.1002/1878-0261.12692CLLDAPK3H3T11histone phosphorylationIbrutinibmRNA processing |
| spellingShingle | Fraser Thomas Katie B. Holmes Sarah Kreuz Peter Hillmen Pascal F. Lefevre DAPK3 participates in the mRNA processing of immediate early genes in chronic lymphocytic leukaemia Molecular Oncology CLL DAPK3 H3T11 histone phosphorylation Ibrutinib mRNA processing |
| title | DAPK3 participates in the mRNA processing of immediate early genes in chronic lymphocytic leukaemia |
| title_full | DAPK3 participates in the mRNA processing of immediate early genes in chronic lymphocytic leukaemia |
| title_fullStr | DAPK3 participates in the mRNA processing of immediate early genes in chronic lymphocytic leukaemia |
| title_full_unstemmed | DAPK3 participates in the mRNA processing of immediate early genes in chronic lymphocytic leukaemia |
| title_short | DAPK3 participates in the mRNA processing of immediate early genes in chronic lymphocytic leukaemia |
| title_sort | dapk3 participates in the mrna processing of immediate early genes in chronic lymphocytic leukaemia |
| topic | CLL DAPK3 H3T11 histone phosphorylation Ibrutinib mRNA processing |
| url | https://doi.org/10.1002/1878-0261.12692 |
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