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CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma
Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many sta...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061728/ https://www.ncbi.nlm.nih.gov/pubmed/36998071 http://dx.doi.org/10.1186/s12943-023-01762-6 |
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author | Thieme, Elana Bruss, Nur Sun, Duanchen Dominguez, Edward C. Coleman, Daniel Liu, Tingting Roleder, Carly Martinez, Melissa Garcia-Mansfield, Krystine Ball, Brian Pirrotte, Patrick Wang, Lili Xia, Zheng Danilov, Alexey V. |
author_facet | Thieme, Elana Bruss, Nur Sun, Duanchen Dominguez, Edward C. Coleman, Daniel Liu, Tingting Roleder, Carly Martinez, Melissa Garcia-Mansfield, Krystine Ball, Brian Pirrotte, Patrick Wang, Lili Xia, Zheng Danilov, Alexey V. |
author_sort | Thieme, Elana |
collection | PubMed |
description | Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-023-01762-6. |
format | Online Article Text |
id | pubmed-10061728 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-100617282023-03-31 CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma Thieme, Elana Bruss, Nur Sun, Duanchen Dominguez, Edward C. Coleman, Daniel Liu, Tingting Roleder, Carly Martinez, Melissa Garcia-Mansfield, Krystine Ball, Brian Pirrotte, Patrick Wang, Lili Xia, Zheng Danilov, Alexey V. Mol Cancer Research Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-023-01762-6. BioMed Central 2023-03-30 /pmc/articles/PMC10061728/ /pubmed/36998071 http://dx.doi.org/10.1186/s12943-023-01762-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Thieme, Elana Bruss, Nur Sun, Duanchen Dominguez, Edward C. Coleman, Daniel Liu, Tingting Roleder, Carly Martinez, Melissa Garcia-Mansfield, Krystine Ball, Brian Pirrotte, Patrick Wang, Lili Xia, Zheng Danilov, Alexey V. CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma |
title | CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma |
title_full | CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma |
title_fullStr | CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma |
title_full_unstemmed | CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma |
title_short | CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma |
title_sort | cdk9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061728/ https://www.ncbi.nlm.nih.gov/pubmed/36998071 http://dx.doi.org/10.1186/s12943-023-01762-6 |
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