Combined Approach to Leukemic Differentiation Using Transcription Factor PU.1-Enhancing Agents
The transcription factor PU.1 (Purine-rich DNA binding, SPI1) is a key regulator of hematopoiesis, whose level is influenced by transcription through its enhancers and its post-transcriptional degradation via microRNA-155 (miR-155). The degree of transcriptional regulation of the <i>PU.1</i...
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| Format: | Article |
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MDPI AG
2022-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/12/6729 |
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| author | Petra Bašová Helena Paszeková Lubomír Minařík Martina Dluhošová Pavel Burda Tomáš Stopka |
| author_facet | Petra Bašová Helena Paszeková Lubomír Minařík Martina Dluhošová Pavel Burda Tomáš Stopka |
| author_sort | Petra Bašová |
| collection | DOAJ |
| description | The transcription factor PU.1 (Purine-rich DNA binding, SPI1) is a key regulator of hematopoiesis, whose level is influenced by transcription through its enhancers and its post-transcriptional degradation via microRNA-155 (miR-155). The degree of transcriptional regulation of the <i>PU.1</i> gene is influenced by repression via DNA methylation, as well as other epigenetic factors, such as those related to progenitor maturation status, which is modulated by the transcription factor Myeloblastosis oncogene (MYB). In this work, we show that combinatorial treatment of acute myeloid leukemia (AML) cells with DNA methylation inhibitors (5-Azacytidine), MYB inhibitors (Celastrol), and anti-miR-155 (AM155) ideally leads to overproduction of PU.1. We also show that PU.1 reactivation can be compensated by miR-155 and that only a combined approach leads to sustained PU.1 derepression, even at the protein level. The triple effect on increasing PU.1 levels in myeloblasts stimulates the myeloid transcriptional program while inhibiting cell survival and proliferation, leading to partial leukemic differentiation. |
| first_indexed | 2024-03-09T23:33:09Z |
| format | Article |
| id | doaj.art-693d1e284c9e4a7c911512e344ee4176 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:33:09Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-693d1e284c9e4a7c911512e344ee41762023-11-23T17:05:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012312672910.3390/ijms23126729Combined Approach to Leukemic Differentiation Using Transcription Factor PU.1-Enhancing AgentsPetra Bašová0Helena Paszeková1Lubomír Minařík2Martina Dluhošová3Pavel Burda4Tomáš Stopka5BIOCEV, 1st Medical Faculty, Charles University, 25250 Vestec, Czech RepublicBIOCEV, 1st Medical Faculty, Charles University, 25250 Vestec, Czech RepublicBIOCEV, 1st Medical Faculty, Charles University, 25250 Vestec, Czech RepublicBIOCEV, 1st Medical Faculty, Charles University, 25250 Vestec, Czech RepublicBIOCEV, 1st Medical Faculty, Charles University, 25250 Vestec, Czech RepublicBIOCEV, 1st Medical Faculty, Charles University, 25250 Vestec, Czech RepublicThe transcription factor PU.1 (Purine-rich DNA binding, SPI1) is a key regulator of hematopoiesis, whose level is influenced by transcription through its enhancers and its post-transcriptional degradation via microRNA-155 (miR-155). The degree of transcriptional regulation of the <i>PU.1</i> gene is influenced by repression via DNA methylation, as well as other epigenetic factors, such as those related to progenitor maturation status, which is modulated by the transcription factor Myeloblastosis oncogene (MYB). In this work, we show that combinatorial treatment of acute myeloid leukemia (AML) cells with DNA methylation inhibitors (5-Azacytidine), MYB inhibitors (Celastrol), and anti-miR-155 (AM155) ideally leads to overproduction of PU.1. We also show that PU.1 reactivation can be compensated by miR-155 and that only a combined approach leads to sustained PU.1 derepression, even at the protein level. The triple effect on increasing PU.1 levels in myeloblasts stimulates the myeloid transcriptional program while inhibiting cell survival and proliferation, leading to partial leukemic differentiation.https://www.mdpi.com/1422-0067/23/12/6729transcription factor PU.1microRNA miR-1555-AzacytidineCelastrol |
| spellingShingle | Petra Bašová Helena Paszeková Lubomír Minařík Martina Dluhošová Pavel Burda Tomáš Stopka Combined Approach to Leukemic Differentiation Using Transcription Factor PU.1-Enhancing Agents International Journal of Molecular Sciences transcription factor PU.1 microRNA miR-155 5-Azacytidine Celastrol |
| title | Combined Approach to Leukemic Differentiation Using Transcription Factor PU.1-Enhancing Agents |
| title_full | Combined Approach to Leukemic Differentiation Using Transcription Factor PU.1-Enhancing Agents |
| title_fullStr | Combined Approach to Leukemic Differentiation Using Transcription Factor PU.1-Enhancing Agents |
| title_full_unstemmed | Combined Approach to Leukemic Differentiation Using Transcription Factor PU.1-Enhancing Agents |
| title_short | Combined Approach to Leukemic Differentiation Using Transcription Factor PU.1-Enhancing Agents |
| title_sort | combined approach to leukemic differentiation using transcription factor pu 1 enhancing agents |
| topic | transcription factor PU.1 microRNA miR-155 5-Azacytidine Celastrol |
| url | https://www.mdpi.com/1422-0067/23/12/6729 |
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