Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA.
Division of Molecular Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cell Rep Med. 2024 Mar 19;5(3):101472. doi: 10.1016/j.xcrm.2024.101472.
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.
间变大细胞淋巴瘤（ALCL）是一种侵袭性的 CD30 T 细胞淋巴瘤，可发生于儿童和成人。大多数 ALCL 肿瘤中均可观察到 ALK 融合转录本或 JAK-STAT 通路中的突变，但肿瘤发生的机制尚未完全阐明。在这里，我们表明，ALCL 中失调的 STAT3 与主要转录因子 BATF3、IRF4 和 IKZF1 共同占据增强子，形成一个核心调控回路，从而建立和维持 ALCL 中的恶性细胞状态。该网络在 ALCL 细胞中的关键下游靶标包括原癌基因 MYC，其需要活性 STAT3 来促进高水平的 MYC 转录。MYC 与与 STAT3 和每个核心调控转录因子相关的增强子区域结合，增强了核心自调控转录电路的活性。因此，STAT3 的激活提供了异常酪氨酸激酶信号和驱动肿瘤发生的核心转录机制之间的关键联系，并在 ALCL 中创造了治疗弱点。
