| Autor: |
Lama Hasan Bou Issa, Léa Fléchon, William Laine, Aicha Ouelkdite, Silvia Gaggero, Adeline Cozzani, Remi Tilmont, Paul Chauvet, Nicolas Gower, Romanos Sklavenitis-Pistofidis, Carine Brinster, Xavier Thuru, Yasmine Touil, Bruno Quesnel, Suman Mitra, Irene M. Ghobrial, Jérôme Kluza, Salomon Manier |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
iScience, Vol 27, Iss 4, Pp 109417- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2589-0042 |
| DOI: |
10.1016/j.isci.2024.109417 |
| Popis: |
Summary: Multiple myeloma (MM) is an incurable hematological malignancy in which MYC alterations contribute to the malignant phenotype. Nevertheless, MYC lacks therapeutic druggability. Here, we leveraged large-scale loss-of-function screens and conducted a small molecule screen to identify genes and pathways with enhanced essentiality correlated with MYC expression. We reported a specific gene dependency in glutaminase (GLS1), essential for the viability and proliferation of MYC overexpressing cells. Conversely, the analysis of isogenic models, as well as cell lines dataset (CCLE) and patient datasets, revealed GLS1 as a non-oncogenic dependency in MYC-driven cells. We functionally delineated the differential modulation of glutamine to maintain mitochondrial function and cellular biosynthesis in MYC overexpressing cells. Furthermore, we observed that pharmaceutical inhibition of NAMPT selectively affects MYC upregulated cells. We demonstrate the effectiveness of combining GLS1 and NAMPT inhibitors, suggesting that targeting glutaminolysis and NAD synthesis may be a promising strategy to target MYC-driven MM. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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