Decitabine mildly attenuates MLL‐rearranged acute lymphoblastic leukemia in vivo, and represents a poor chemo‐sensitizer
Abstract MLL‐rearranged acute lymphoblastic leukemia (ALL) represents a highly aggressive ALL subtype, characterized by aberrant DNA methylation patterns. DNA methyltransferase inhibitors, such as decitabine have previously been demonstrated to be effective in eradicating MLL‐rearranged ALL cells in...
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| Format: | Article |
| Language: | English |
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Wiley
2020-11-01
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| Series: | eJHaem |
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| Online Access: | https://doi.org/10.1002/jha2.81 |
| _version_ | 1797739942146736128 |
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| author | Pauline Schneider Patricia Garrido Castro Sandra M. Pinhanços Mark Kerstjens Eddy H. vanRoon Anke H.W. Essing M. Emmy M. Dolman Jan J. Molenaar Rob Pieters Ronald W. Stam |
| author_facet | Pauline Schneider Patricia Garrido Castro Sandra M. Pinhanços Mark Kerstjens Eddy H. vanRoon Anke H.W. Essing M. Emmy M. Dolman Jan J. Molenaar Rob Pieters Ronald W. Stam |
| author_sort | Pauline Schneider |
| collection | DOAJ |
| description | Abstract MLL‐rearranged acute lymphoblastic leukemia (ALL) represents a highly aggressive ALL subtype, characterized by aberrant DNA methylation patterns. DNA methyltransferase inhibitors, such as decitabine have previously been demonstrated to be effective in eradicating MLL‐rearranged ALL cells in vitro. Here, we assessed the in vivo anti‐leukemic potential of low‐dose DNA methyltransferase inhibitor decitabine using a xenograft mouse model of human MLL‐rearranged ALL. Furthermore, we explored whether prolonged exposure to low‐dose decitabine could chemo‐sensitize MLL‐rearranged ALL cells toward conventional chemotherapy as well as other known epigenetic‐based and anti‐neoplastic compounds. Our data reveal that decitabine prolonged survival in xenograft mice of MLL‐rearranged ALL by 8.5 days (P = .0181), but eventually was insufficient to prevent leukemia out‐growth, based on the examination of the MLLAF4 cell line SEM. Furthermore, we observe that prolonged pretreatment of low‐dose decitabine mildly sensitized toward the conventional drugs prednisolone, vincristine, daunorubicin, asparaginase, and cytarabine in a panel of MLL‐rearranged cell lines. Additionally, we assessed synergistic effects of decitabine with other epigenetic‐based or anticancer drugs using high‐throughput drug library screens. Validation of the top hits, including histone deacetylase inhibitor panobinostat, BCL2 inhibitor Venetoclax, MEK inhibitor pimasertib, and receptor tyrosine kinase foretinib, revealed additive and moderate synergistic effects for the combination of each drug together with decitabine in a cell line‐dependent manner. |
| first_indexed | 2024-03-12T14:05:25Z |
| format | Article |
| id | doaj.art-17ab3a3cd77a4a4f9267630c85d65ee2 |
| institution | Directory Open Access Journal |
| issn | 2688-6146 |
| language | English |
| last_indexed | 2024-03-12T14:05:25Z |
| publishDate | 2020-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | eJHaem |
| spelling | doaj.art-17ab3a3cd77a4a4f9267630c85d65ee22023-08-21T14:10:56ZengWileyeJHaem2688-61462020-11-011252753610.1002/jha2.81Decitabine mildly attenuates MLL‐rearranged acute lymphoblastic leukemia in vivo, and represents a poor chemo‐sensitizerPauline Schneider0Patricia Garrido Castro1Sandra M. Pinhanços2Mark Kerstjens3Eddy H. vanRoon4Anke H.W. Essing5M. Emmy M. Dolman6Jan J. Molenaar7Rob Pieters8Ronald W. Stam9Princess Máxima Center for Pediatric Oncology Utrecht The NetherlandsPrincess Máxima Center for Pediatric Oncology Utrecht The NetherlandsPrincess Máxima Center for Pediatric Oncology Utrecht The NetherlandsDepartment of Pediatric Hematology/Oncology Erasmus MC ‐ Sophia Children's Hospital Rotterdam The NetherlandsDepartment of Pediatric Hematology/Oncology Erasmus MC ‐ Sophia Children's Hospital Rotterdam The NetherlandsPrincess Máxima Center for Pediatric Oncology Utrecht The NetherlandsPrincess Máxima Center for Pediatric Oncology Utrecht The NetherlandsPrincess Máxima Center for Pediatric Oncology Utrecht The NetherlandsPrincess Máxima Center for Pediatric Oncology Utrecht The NetherlandsPrincess Máxima Center for Pediatric Oncology Utrecht The NetherlandsAbstract MLL‐rearranged acute lymphoblastic leukemia (ALL) represents a highly aggressive ALL subtype, characterized by aberrant DNA methylation patterns. DNA methyltransferase inhibitors, such as decitabine have previously been demonstrated to be effective in eradicating MLL‐rearranged ALL cells in vitro. Here, we assessed the in vivo anti‐leukemic potential of low‐dose DNA methyltransferase inhibitor decitabine using a xenograft mouse model of human MLL‐rearranged ALL. Furthermore, we explored whether prolonged exposure to low‐dose decitabine could chemo‐sensitize MLL‐rearranged ALL cells toward conventional chemotherapy as well as other known epigenetic‐based and anti‐neoplastic compounds. Our data reveal that decitabine prolonged survival in xenograft mice of MLL‐rearranged ALL by 8.5 days (P = .0181), but eventually was insufficient to prevent leukemia out‐growth, based on the examination of the MLLAF4 cell line SEM. Furthermore, we observe that prolonged pretreatment of low‐dose decitabine mildly sensitized toward the conventional drugs prednisolone, vincristine, daunorubicin, asparaginase, and cytarabine in a panel of MLL‐rearranged cell lines. Additionally, we assessed synergistic effects of decitabine with other epigenetic‐based or anticancer drugs using high‐throughput drug library screens. Validation of the top hits, including histone deacetylase inhibitor panobinostat, BCL2 inhibitor Venetoclax, MEK inhibitor pimasertib, and receptor tyrosine kinase foretinib, revealed additive and moderate synergistic effects for the combination of each drug together with decitabine in a cell line‐dependent manner.https://doi.org/10.1002/jha2.81acute lymphoblastic leukemiachemo‐sensitizerdecitabineDNA demethylating agentKMT2AMLL |
| spellingShingle | Pauline Schneider Patricia Garrido Castro Sandra M. Pinhanços Mark Kerstjens Eddy H. vanRoon Anke H.W. Essing M. Emmy M. Dolman Jan J. Molenaar Rob Pieters Ronald W. Stam Decitabine mildly attenuates MLL‐rearranged acute lymphoblastic leukemia in vivo, and represents a poor chemo‐sensitizer eJHaem acute lymphoblastic leukemia chemo‐sensitizer decitabine DNA demethylating agent KMT2A MLL |
| title | Decitabine mildly attenuates MLL‐rearranged acute lymphoblastic leukemia in vivo, and represents a poor chemo‐sensitizer |
| title_full | Decitabine mildly attenuates MLL‐rearranged acute lymphoblastic leukemia in vivo, and represents a poor chemo‐sensitizer |
| title_fullStr | Decitabine mildly attenuates MLL‐rearranged acute lymphoblastic leukemia in vivo, and represents a poor chemo‐sensitizer |
| title_full_unstemmed | Decitabine mildly attenuates MLL‐rearranged acute lymphoblastic leukemia in vivo, and represents a poor chemo‐sensitizer |
| title_short | Decitabine mildly attenuates MLL‐rearranged acute lymphoblastic leukemia in vivo, and represents a poor chemo‐sensitizer |
| title_sort | decitabine mildly attenuates mll rearranged acute lymphoblastic leukemia in vivo and represents a poor chemo sensitizer |
| topic | acute lymphoblastic leukemia chemo‐sensitizer decitabine DNA demethylating agent KMT2A MLL |
| url | https://doi.org/10.1002/jha2.81 |
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