MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma.

Abstract

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 (<i>FLI1, BCL11A</i>) or B-cell development and activation (<i>PAX5, CDKN1B, JAK2, CARD11</i>) and found a number of context-specific dependencies including oncogene addiction in cell lines with <i>TCF3</i>/<i>ID3</i> or <i>MYD88</i> mutation. The strongest genotype-phenotype association was seen for <i>TP53</i>. MDM4, a negative regulator of <i>TP53</i>, was essential in <i>TP53</i> wild-type (TP53wt) Burkitt lymphoma cell lines. <i>MDM4</i> 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 <i>MDM4</i> locus, and showed elevated MDM4 mRNA levels. 1q gain was associated with TP53wt across 789 cancer cell lines and <i>MDM4</i> 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.