Hüllein, Jennifer; Słabicki, Mikołaj; Rosolowski, Maciej; Jethwa, Alexander; Habringer, Stefan; Tomska, Katarzyna; Kurilov, Roma; Lu, Junyan; Scheinost, Sebastian; Wagener, Rabea; Huang, Zhiqin; Lukas, Marina; Yavorska, Olena; Helfrich, Hanne; Scholtysik, René; Bonneau, Kyle; Tedesco, Donato; Küppers, Ralf; Klapper, Wolfram; Pott, Christiane; Stilgenbauer, Stephan; Burkhardt, Birgit; Löffler, Markus; Trümper, Lorenz H; Hummel, Michael; Brors, Benedikt; Zapatka, Marc; Siebert, Reiner; Kreuz, Markus; Keller, Ulrich; Huber, Wolfgang; Zenz, Thorsten     «

Hüllein, Jennifer; Słabicki, Mikołaj; Rosolowski, Maciej; Jethwa, Alexander; Habringer, Stefan; Tomska, Katarzyna; Kurilov, Roma; Lu, Junyan; Scheinost, Sebastian; Wagener, Rabea; Huang, Zhiqin; Lukas, Marina; Yavorska, Olena; Helfrich, Hanne; Scholtysik, René; Bonneau, Kyle; Tedesco, Donato; Küppers, Ralf; Klapper, Wolfram; Pott, Christiane; Stilgenbauer, Stephan; Burkhardt, Birgit; Löffler, Markus; Trümper, Lorenz H; Hummel, Michael; Brors, Benedikt; Zapatka, Marc; Siebert, Reiner; Kreuz, Mark...     »

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.      «

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 wit...     »