Uncovering NOTCH1 as a Promising Target in the Treatment of <i>MLL</i>-Rearranged Leukemia

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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Bibliographic Details
Main Authors: Jacqueline Fischer, Estelle Erkner, Rahel Fitzel, Pia Radszuweit, Hildegard Keppeler, Fulya Korkmaz, Giovanni Roti, Claudia Lengerke, Dominik Schneidawind, Corina Schneidawind
Format: Article
Language:English
Published: MDPI AG 2023-09-01
Series:International Journal of Molecular Sciences
Subjects:
<i>MLL</i>-rearranged leukemia
NOTCH1
CRISPR/Cas9
SERCA inhibitor
targeted therapy
Online Access:https://www.mdpi.com/1422-0067/24/19/14466
Description
Summary:<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.
ISSN:1661-6596
1422-0067

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