Abstract
Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.
Highlights
Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL
We find BATF3 and IL-2 receptor (IL2R) components are among the top SE hits, prompting us to analyze the link between BATF3 and IL-2 receptor (IL-2R) components in ALCL cells, and to explore the biological function of the IL-2/IL-2R system in ALCL in detail
We defined 538 and 722 SEs in Karpas-299 and Mac-1 cell lines (Fig. 1a, b), respectively. 225 genes associated with SEs were shared between both cell lines (Fig. 1c and Supplementary Table 1)
Summary
Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. Despite implementation of targeted treatment strategies such as CD30 antibody-drug conjugates (ADCs) into up-front treatment regimens[4], the prognosis of some particular systemic ALCL subtypes is unsatisfactory[5], and there is an unmet medical need for effective treatment options in the case of relapsed and refractory disease[6,7]. Super-enhancers (SEs) are genomic regions bound by large clusters of regulatory elements resulting in high-level gene expression of the respective genes, which are marked by extensive stretches of histone 3 lysine 27 acetylation (H3K27ac)[21,22] and help to define unique tumor dependencies and therapeutically relevant vulnerabilities[23]. We find BATF3 and IL2R components are among the top SE hits, prompting us to analyze the link between BATF3 and IL-2R components in ALCL cells, and to explore the biological function of the IL-2/IL-2R system in ALCL in detail
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
