Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.
- MeSH
- anaplastická lymfomová kináza genetika metabolismus MeSH
- anaplastický velkobuněčný lymfom * genetika metabolismus patologie MeSH
- dítě MeSH
- dospělí MeSH
- Janus kinasy metabolismus MeSH
- karcinogeneze genetika MeSH
- lidé MeSH
- nádorová transformace buněk MeSH
- signální transdukce * genetika MeSH
- transkripční faktor STAT3 genetika MeSH
- transkripční faktory STAT metabolismus MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- anaplastická lymfomová kináza MeSH
- Janus kinasy MeSH
- STAT3 protein, human MeSH Prohlížeč
- transkripční faktor STAT3 MeSH
- transkripční faktory STAT MeSH
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.
- MeSH
- anaplastický velkobuněčný lymfom farmakoterapie genetika metabolismus patologie MeSH
- antigen Ki-1 genetika metabolismus MeSH
- imunokonjugáty farmakologie MeSH
- interleukin-15 farmakologie MeSH
- interleukin-2 farmakologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- receptor interleukinu-2 - alfa-podjednotka genetika imunologie metabolismus MeSH
- receptory interleukinu-2 genetika imunologie metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- regulační oblasti nukleových kyselin MeSH
- represorové proteiny genetika metabolismus MeSH
- signální transdukce účinky léků MeSH
- transkripční faktory bZIP genetika metabolismus MeSH
- viabilita buněk účinky léků MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antigen Ki-1 MeSH
- BATF3 protein, human MeSH Prohlížeč
- IL2RA protein, human MeSH Prohlížeč
- imunokonjugáty MeSH
- interleukin-15 MeSH
- interleukin-2 MeSH
- receptor interleukinu-2 - alfa-podjednotka MeSH
- receptory interleukinu-2 MeSH
- represorové proteiny MeSH
- transkripční faktory bZIP MeSH
