Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma [ChIP-Seq]

Systemic anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma comprising ALK-positive (ALK+) and ALK-negative (ALK-) as well as breast implant-associated (BIA)-ALCL. The prognosis for ALCL, ALK- in particular is poor, and already in second line there is an unmet medical need for effective treatment options. To identify genes defining ALCL cell state and dependencies, we here started by an unbiased characterization of super-enhancer regions by genome-wide H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq). We identified, in addition to known key regulators, the AP-1 transcription factor member BATF3 and IL-2 receptor (IL2R) components among the genes with most extensively H3K27-acetylated regulatory regions. Consistently, specific and high-level expression of the IL-2R subunits, IL-2Ra, IL-2Rß and IL-2R? in ALCL correlate with BATF3 expression. Confirming a regulatory link, expression of IL-2R subunits decreases following BATF3 knockout, and BATF3 is recruited to AP-1 sites in IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate growth of ALCL cells and activate STAT1, STAT5 and ERK, but not STAT3. In line, strong IL-2Ra expression in ALCL patients is linked to more aggressive clinical presentation. Finally, we demonstrate highly efficient killing of ALCL cells by an IL-2Ra-targeting antibody-drug conjugate in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R module for ALCL biology and identify IL-2Ra as the target of a promising treatment strategy for ALCL. Overall design: Genome binding/occupancy profiling by high throughput sequencing in anaplastic large cell lymphoma cell lines