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Targeting MYC in combination with epigenetic regulators induces synergistic anti-leukemic effects in MLLr leukemia and simultaneously improves immunity
MLL rearranged (MLLr) leukemias are associated with a poor prognosis and a limited response to conventional therapies. Moreover, chemotherapies result in severe side effects with significant impairment of the immune system. Therefore, the identification of novel treatment strategies is mandatory. Re...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192941/ https://www.ncbi.nlm.nih.gov/pubmed/37148657 http://dx.doi.org/10.1016/j.neo.2023.100902 |
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author | Fitzel, Rahel Secker-Grob, Kathy-Ann Keppeler, Hildegard Korkmaz, Fulya Schairer, Rebekka Erkner, Estelle Schneidawind, Dominik Lengerke, Claudia Hentrich, Thomas Schulze-Hentrich, Julia M. Schneidawind, Corina |
author_facet | Fitzel, Rahel Secker-Grob, Kathy-Ann Keppeler, Hildegard Korkmaz, Fulya Schairer, Rebekka Erkner, Estelle Schneidawind, Dominik Lengerke, Claudia Hentrich, Thomas Schulze-Hentrich, Julia M. Schneidawind, Corina |
author_sort | Fitzel, Rahel |
collection | PubMed |
description | MLL rearranged (MLLr) leukemias are associated with a poor prognosis and a limited response to conventional therapies. Moreover, chemotherapies result in severe side effects with significant impairment of the immune system. Therefore, the identification of novel treatment strategies is mandatory. Recently, we developed a human MLLr leukemia model by inducing chromosomal rearrangements in CD34+ cells using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9. This MLLr model authentically mimics patient leukemic cells and can be used as a platform for novel treatment strategies. RNA sequencing of our model revealed MYC as one of the most important key drivers to promote oncogenesis. However, in clinical trials the BRD4 inhibitor JQ-1 leading to indirect blocking of the MYC pathway shows only modest activity. We and others previously reported that epigenetic drugs targeting MAT2A or PRMT5 promote cell death in MLLr cells. Therefore, we use these drugs in combination with JQ-1 leading to augmented anti-leukemic effects. Moreover, we found activation of T, NK and iNKT cells, release of immunomodulatory cytokines and downregulation of the PD-1/PD-L1 axis upon inhibitor treatment leading to improved cytotoxicity. In summary, the inhibition of MYC and MAT2A or PRMT5 drives robust synergistic anti-leukemic activity in MLLr leukemia. Moreover, the immune system is concomitantly activated upon combinatorial inhibitor treatment, hereby further augmenting the therapeutic efficiency. |
format | Online Article Text |
id | pubmed-10192941 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-101929412023-05-19 Targeting MYC in combination with epigenetic regulators induces synergistic anti-leukemic effects in MLLr leukemia and simultaneously improves immunity Fitzel, Rahel Secker-Grob, Kathy-Ann Keppeler, Hildegard Korkmaz, Fulya Schairer, Rebekka Erkner, Estelle Schneidawind, Dominik Lengerke, Claudia Hentrich, Thomas Schulze-Hentrich, Julia M. Schneidawind, Corina Neoplasia Original Research MLL rearranged (MLLr) leukemias are associated with a poor prognosis and a limited response to conventional therapies. Moreover, chemotherapies result in severe side effects with significant impairment of the immune system. Therefore, the identification of novel treatment strategies is mandatory. Recently, we developed a human MLLr leukemia model by inducing chromosomal rearrangements in CD34+ cells using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9. This MLLr model authentically mimics patient leukemic cells and can be used as a platform for novel treatment strategies. RNA sequencing of our model revealed MYC as one of the most important key drivers to promote oncogenesis. However, in clinical trials the BRD4 inhibitor JQ-1 leading to indirect blocking of the MYC pathway shows only modest activity. We and others previously reported that epigenetic drugs targeting MAT2A or PRMT5 promote cell death in MLLr cells. Therefore, we use these drugs in combination with JQ-1 leading to augmented anti-leukemic effects. Moreover, we found activation of T, NK and iNKT cells, release of immunomodulatory cytokines and downregulation of the PD-1/PD-L1 axis upon inhibitor treatment leading to improved cytotoxicity. In summary, the inhibition of MYC and MAT2A or PRMT5 drives robust synergistic anti-leukemic activity in MLLr leukemia. Moreover, the immune system is concomitantly activated upon combinatorial inhibitor treatment, hereby further augmenting the therapeutic efficiency. Neoplasia Press 2023-05-04 /pmc/articles/PMC10192941/ /pubmed/37148657 http://dx.doi.org/10.1016/j.neo.2023.100902 Text en © 2023 The Authors. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Fitzel, Rahel Secker-Grob, Kathy-Ann Keppeler, Hildegard Korkmaz, Fulya Schairer, Rebekka Erkner, Estelle Schneidawind, Dominik Lengerke, Claudia Hentrich, Thomas Schulze-Hentrich, Julia M. Schneidawind, Corina Targeting MYC in combination with epigenetic regulators induces synergistic anti-leukemic effects in MLLr leukemia and simultaneously improves immunity |
title | Targeting MYC in combination with epigenetic regulators induces synergistic anti-leukemic effects in MLLr leukemia and simultaneously improves immunity |
title_full | Targeting MYC in combination with epigenetic regulators induces synergistic anti-leukemic effects in MLLr leukemia and simultaneously improves immunity |
title_fullStr | Targeting MYC in combination with epigenetic regulators induces synergistic anti-leukemic effects in MLLr leukemia and simultaneously improves immunity |
title_full_unstemmed | Targeting MYC in combination with epigenetic regulators induces synergistic anti-leukemic effects in MLLr leukemia and simultaneously improves immunity |
title_short | Targeting MYC in combination with epigenetic regulators induces synergistic anti-leukemic effects in MLLr leukemia and simultaneously improves immunity |
title_sort | targeting myc in combination with epigenetic regulators induces synergistic anti-leukemic effects in mllr leukemia and simultaneously improves immunity |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192941/ https://www.ncbi.nlm.nih.gov/pubmed/37148657 http://dx.doi.org/10.1016/j.neo.2023.100902 |
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