Uncovering NOTCH1 as a Promising Target in the Treatment of <i>MLL</i>-Rearranged Leukemia
<i>MLL</i> rearrangement (<i>MLL</i>r) is responsible for the development of acute leukemias with poor outcomes. Therefore, new therapeutic approaches are urgently needed. The NOTCH1 pathway plays a critical role in the pathogenesis of many cancers including acute leukemia. U...
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MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/19/14466 |
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| author | Jacqueline Fischer Estelle Erkner Rahel Fitzel Pia Radszuweit Hildegard Keppeler Fulya Korkmaz Giovanni Roti Claudia Lengerke Dominik Schneidawind Corina Schneidawind |
| author_facet | Jacqueline Fischer Estelle Erkner Rahel Fitzel Pia Radszuweit Hildegard Keppeler Fulya Korkmaz Giovanni Roti Claudia Lengerke Dominik Schneidawind Corina Schneidawind |
| author_sort | Jacqueline Fischer |
| collection | DOAJ |
| description | <i>MLL</i> rearrangement (<i>MLL</i>r) is responsible for the development of acute leukemias with poor outcomes. Therefore, new therapeutic approaches are urgently needed. The NOTCH1 pathway plays a critical role in the pathogenesis of many cancers including acute leukemia. Using a CRISPR/Cas9 <i>MLL-AF4/-AF9</i> translocation model, the newly developed NOTCH1 inhibitor CAD204520 with less toxic side effects allowed us to unravel the impact of NOTCH1 as a pathogenic driver and potential therapeutic target in <i>MLL</i>r leukemia. RNA sequencing (RNA-seq) and RT-qPCR of our <i>MLL</i>r model and <i>MLL</i>r cell lines showed the NOTCH1 pathway was overexpressed and activated. Strikingly, we confirmed this elevated expression level in leukemia patients. We also demonstrated that CAD204520 treatment of <i>MLL</i>r cells significantly reduces <i>NOTCH1</i> and its target genes as well as NOTCH1 receptor expression. This was not observed with a comparable cytarabine treatment, indicating the specificity of the small molecule. Accordingly, treatment with CAD204520 resulted in dose-dependent reduced proliferation and viability, increased apoptosis, and the induction of cell cycle arrest via the downregulation of MLL and NOTCH1 target genes. In conclusion, our findings uncover the oncogenic relevance of the NOTCH1 pathway in <i>MLL</i>r leukemia. Its inhibition leads to specific anti-leukemic effects and paves the way for further evaluation in clinical settings. |
| first_indexed | 2024-03-10T21:43:22Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:43:22Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-141c8ec1797b428787335dc5fdca4e832023-11-19T14:27:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124191446610.3390/ijms241914466Uncovering NOTCH1 as a Promising Target in the Treatment of <i>MLL</i>-Rearranged LeukemiaJacqueline Fischer0Estelle Erkner1Rahel Fitzel2Pia Radszuweit3Hildegard Keppeler4Fulya Korkmaz5Giovanni Roti6Claudia Lengerke7Dominik Schneidawind8Corina Schneidawind9Department of Medicine II, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyDepartment of Medicine II, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyDepartment of Medicine II, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyDepartment of Medicine II, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyDepartment of Medicine II, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyDepartment of Medicine II, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyDepartment of Medicine and Surgery, University of Parma, 43121 Parma, ItalyDepartment of Medicine II, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyDepartment of Medicine II, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyDepartment of Medicine II, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, Germany<i>MLL</i> rearrangement (<i>MLL</i>r) is responsible for the development of acute leukemias with poor outcomes. Therefore, new therapeutic approaches are urgently needed. The NOTCH1 pathway plays a critical role in the pathogenesis of many cancers including acute leukemia. Using a CRISPR/Cas9 <i>MLL-AF4/-AF9</i> translocation model, the newly developed NOTCH1 inhibitor CAD204520 with less toxic side effects allowed us to unravel the impact of NOTCH1 as a pathogenic driver and potential therapeutic target in <i>MLL</i>r leukemia. RNA sequencing (RNA-seq) and RT-qPCR of our <i>MLL</i>r model and <i>MLL</i>r cell lines showed the NOTCH1 pathway was overexpressed and activated. Strikingly, we confirmed this elevated expression level in leukemia patients. We also demonstrated that CAD204520 treatment of <i>MLL</i>r cells significantly reduces <i>NOTCH1</i> and its target genes as well as NOTCH1 receptor expression. This was not observed with a comparable cytarabine treatment, indicating the specificity of the small molecule. Accordingly, treatment with CAD204520 resulted in dose-dependent reduced proliferation and viability, increased apoptosis, and the induction of cell cycle arrest via the downregulation of MLL and NOTCH1 target genes. In conclusion, our findings uncover the oncogenic relevance of the NOTCH1 pathway in <i>MLL</i>r leukemia. Its inhibition leads to specific anti-leukemic effects and paves the way for further evaluation in clinical settings.https://www.mdpi.com/1422-0067/24/19/14466<i>MLL</i>-rearranged leukemiaNOTCH1CRISPR/Cas9SERCA inhibitortargeted therapy |
| spellingShingle | Jacqueline Fischer Estelle Erkner Rahel Fitzel Pia Radszuweit Hildegard Keppeler Fulya Korkmaz Giovanni Roti Claudia Lengerke Dominik Schneidawind Corina Schneidawind Uncovering NOTCH1 as a Promising Target in the Treatment of <i>MLL</i>-Rearranged Leukemia International Journal of Molecular Sciences <i>MLL</i>-rearranged leukemia NOTCH1 CRISPR/Cas9 SERCA inhibitor targeted therapy |
| title | Uncovering NOTCH1 as a Promising Target in the Treatment of <i>MLL</i>-Rearranged Leukemia |
| title_full | Uncovering NOTCH1 as a Promising Target in the Treatment of <i>MLL</i>-Rearranged Leukemia |
| title_fullStr | Uncovering NOTCH1 as a Promising Target in the Treatment of <i>MLL</i>-Rearranged Leukemia |
| title_full_unstemmed | Uncovering NOTCH1 as a Promising Target in the Treatment of <i>MLL</i>-Rearranged Leukemia |
| title_short | Uncovering NOTCH1 as a Promising Target in the Treatment of <i>MLL</i>-Rearranged Leukemia |
| title_sort | uncovering notch1 as a promising target in the treatment of i mll i rearranged leukemia |
| topic | <i>MLL</i>-rearranged leukemia NOTCH1 CRISPR/Cas9 SERCA inhibitor targeted therapy |
| url | https://www.mdpi.com/1422-0067/24/19/14466 |
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