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MDM4 is targeted by 1q gain and drives disease in Burkitt Lymphoma

Oncogenic MYC activation promotes proliferation in Burkitt lymphoma, but also induces cell-cycle arrest and apoptosis mediated by p53, a tumor suppressor that is mutated in 40% of Burkitt lymphoma cases. To identify molecular dependencies in Burkitt lymphoma, we performed RNAi-based, loss-of-functio...

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Main Authors: Hüllein, Jennifer (Author) , Słabicki, Mikołaj (Author) , Rosolowski, Maciej (Author) , Jethwa, Alexander (Author) , Habringer, Stefan (Author) , Tomska, Katarzyna (Author) , Kurilov, Roma (Author) , Lu, Junyan (Author) , Scheinost, Sebastian (Author) , Wagener, Rabea (Author) , Huang, Zhiqin (Author) , Lukas, Marina (Author) , Yavorska, Olena (Author) , Helfrich, Hanne (Author) , Scholtysik, René (Author) , Bonneau, Kyle (Author) , Tedesco, Donato (Author) , Küppers, Ralf (Author) , Klapper, Wolfram (Author) , Pott, Christiane (Author) , Stilgenbauer, Stephan (Author) , Burkhardt, Birgit (Author) , Löffler, Markus (Author) , Trümper, Lorenz H. (Author) , Hummel, Michael (Author) , Brors, Benedikt (Author) , Zapatka, Marc (Author) , Siebert, Reiner (Author) , Kreuz, Markus (Author) , Keller, Ulrich (Author) , Huber, Wolfgang (Author) , Zenz, Thorsten (Author)
Format: Article (Journal)
Language:English
Published: June 2019
In: Cancer research
Year: 2019, Volume: 79, Issue: 12, Pages: 3125-3138
ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-18-3438
Online Access:Verlag, Volltext: https://doi.org/10.1158/0008-5472.CAN-18-3438
Verlag: https://cancerres.aacrjournals.org/content/79/12/3125
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Author Notes:Jennifer Hüllein, Mikołaj Słabicki, Maciej Rosolowski, Alexander Jethwa, Stefan Habringer, Katarzyna Tomska, Roma Kurilov, Junyan Lu, Sebastian Scheinost, Rabea Wagener, Zhiqin Huang, Marina Lukas, Olena Yavorska, Hanne Helfrich, René Scholtysik, Kyle Bonneau, Donato Tedesco, Ralf Küppers, Wolfram Klapper, Christiane Pott, Stephan Stilgenbauer, Birgit Burkhardt, Markus Löffler, Lorenz H. Trümper, Michael Hummel, Benedikt Brors, Marc Zapatka, Reiner Siebert, Markus Kreuz, Ulrich Keller, Wolfgang Huber, and Thorsten Zenz

MARC

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245 1 0 |a MDM4 is targeted by 1q gain and drives disease in Burkitt Lymphoma  |c Jennifer Hüllein, Mikołaj Słabicki, Maciej Rosolowski, Alexander Jethwa, Stefan Habringer, Katarzyna Tomska, Roma Kurilov, Junyan Lu, Sebastian Scheinost, Rabea Wagener, Zhiqin Huang, Marina Lukas, Olena Yavorska, Hanne Helfrich, René Scholtysik, Kyle Bonneau, Donato Tedesco, Ralf Küppers, Wolfram Klapper, Christiane Pott, Stephan Stilgenbauer, Birgit Burkhardt, Markus Löffler, Lorenz H. Trümper, Michael Hummel, Benedikt Brors, Marc Zapatka, Reiner Siebert, Markus Kreuz, Ulrich Keller, Wolfgang Huber, and Thorsten Zenz 
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520 |a Oncogenic MYC activation promotes proliferation in Burkitt lymphoma, but also induces cell-cycle arrest and apoptosis mediated by p53, a tumor suppressor that is mutated in 40% of Burkitt lymphoma cases. To identify molecular dependencies in Burkitt lymphoma, we performed RNAi-based, loss-of-function screening in eight Burkitt lymphoma cell lines and integrated non-Burkitt lymphoma RNAi screens and genetic data. We identified 76 genes essential to Burkitt lymphoma, including genes associated with hematopoietic cell differentiation (FLI1, BCL11A) or B-cell development and activation (PAX5, CDKN1B, JAK2, CARD11) and found a number of context-specific dependencies including oncogene addiction in cell lines with TCF3/ID3 or MYD88 mutation. The strongest genotype-phenotype association was seen for TP53. MDM4, a negative regulator of TP53, was essential in TP53 wild-type (TP53wt) Burkitt lymphoma cell lines. MDM4 knockdown activated p53, induced cell-cycle arrest, and decreased tumor growth in a xenograft model in a p53-dependent manner. Small molecule inhibition of the MDM4-p53 interaction was effective only in TP53wt Burkitt lymphoma cell lines. Moreover, primary TP53wt Burkitt lymphoma samples frequently acquired gains of chromosome 1q, which includes the MDM4 locus, and showed elevated MDM4 mRNA levels. 1q gain was associated with TP53wt across 789 cancer cell lines and MDM4 was essential in the TP53wt-context in 216 cell lines representing 19 cancer entities from the Achilles Project. Our findings highlight the critical role of p53 as a tumor suppressor in Burkitt lymphoma and identify MDM4 as a functional target of 1q gain in a wide range of cancers that is therapeutically targetable. - Significance: Targeting MDM4 to alleviate degradation of p53 can be exploited therapeutically across Burkitt lymphoma and other cancers with wild-type p53 harboring 1q gain, the most frequent copy number alteration in cancer. 
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