Anaplastic large cell lymphoma (ALCL), a type of aggressive CD30+ T-cell lymphoma, presents a formidable challenge in oncology due to its complex genetic underpinnings and resistance to conventional therapies. Researchers led by Professor Thomas Look at the Dana-Farber Cancer Institute and Boston Children’s Hospital have elucidated crucial mechanisms in ALCL’s pathology, providing a potential pathway for targeted therapies. Their findings, published in Cell Reports Medicine, reveal how STAT3, a key signaling protein, integrates with core transcriptional regulators to sustain the malignant state in ALCL.
The research team, including Dr. Nicole Prutsch, Dr. Brian Abraham, Dr. Mark Zimmerman, and colleagues, embarked on this study to understand the precise role of STAT3 in ALCL. Their collaborative efforts spanned institutions including St. Jude Children’s Research Hospital, the University of Cambridge, and the Medical University of Vienna as well as the Dana Farber Cancer Institute. The study was published in the peer-reviewed journal Cell Reports Medicine.
ALCL is frequently driven by chromosomal rearrangements that activate the ALK tyrosine kinase or by other mutations that lead to continuous activation of the JAK-STAT signaling pathway. Professor Look and his team discovered that in ALCL cells, actyivated STAT3 binds together with other key transcription factors—BATF3, IRF4, and IKZF1—to form a core regulatory circuit (CRC) that promotes cancer cell survival and proliferation. “Our research demonstrated that ALCL cells are highly dependent on a small group of core regulatory transcription factors. Targeting these dependencies opens new avenues for therapeutic intervention,” said Dr. Zimmerman.
The team used chromatin immunoprecipitation sequencing (ChIP-seq) to map enhancer regions in ALCL cells, identifying a conserved set of super-enhancers associated with genes like BATF3, IRF4, and IKZF1. These regions were highly enriched for H3K27ac, a histone modification characteristic of active enhancers, underscoring the role of the transcription factors encoded by these genes in driving high levels of expression of an extended gene program critical for the malignant phenotype. Moreover, genome-wide occupancy analysis showed that STAT3, after activation by the ALK kinase, collaborates with these CRC transcription factors at super-enhancers, ensuring sustained expression of the oncogenic genes.
The study highlighted that STAT3, although not meeting the typical criteria for a CRC component due to the absence of a super-enhancer driving its expression, plays a pivotal role as a signal-responsive transcription factor. Once activated by tyrosine kinase signaling, STAT3 works in tandem with the CRC to regulate the expression of MYC, a well-known oncogene. “Our findings suggest that STAT3, along with CRC transcription factors, drives the oncogenic gene expression program in ALCL,” noted Dr. Abraham.
Professor Look emphasized the long-term significance of their research, stating, “My laboratory discovered the ALK gene and the NPM-ALK fusion gene in 1994, which provides the activated tyrosine kinase signaling that activates STAT3, as highlighted in our studies reported in the current paper 30 years later, providing a key mechanism of transformation in a large percentage of ALCLs that harbor the t(2;5) chormosomal translocation.”
In functional assays, the researchers demonstrated that disrupting any single component of the CRC significantly impaired ALCL cell growth and viability. Particularly, pharmacologic degradation of IKZF1 led to reduced cell growth, emphasizing its essential role in upregulating the CRC that is essential for ALCL cell proliferation and survival. Additionally, the team showed that STAT3 inhibitors, such as STAT3-IN-3 and Stattic, effectively reduced ALCL cell viability, and their combination with IKZF1 degraders yielded even more substantial anti-tumor effects.
One of the study’s critical insights was the interaction between STAT3 and MYC. By using ChIP-seq, the researchers found that STAT3 binds to the super-enhancer regulatory regions of the MYC gene, which produces high levels of the MYC protein, which then collaborates with CRC transcription factors to maintain high MYC expression levels. This interplay underscores the therapeutic potential of targeting STAT3 in ALCL, especially in cases resistant to ALK inhibitors. “By demonstrating that STAT3 activation is necessary and sufficient for MYC expression and ALCL cell survival, we provide a strong rationale for developing STAT3-targeted therapies,” added Professor Look.
In conclusion, this study sheds light on the intricate regulatory networks sustaining ALCL and identifies STAT3 as a linchpin in the oncogenic process. The collaborative efforts of the research team have paved the way for novel therapeutic strategies targeting the interconnected transcriptional dependencies in ALCL. As Professor Look stated, “Our work offers critical insights into ALCL’s molecular biology, guiding future research towards more effective treatments.”
Journal Reference
Prutsch, N., He, S., Berezovskaya, A., Durbin, A. D., Dharia, N. V., Maher, K. A., … & Look, A. T. (2024). STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuitry of anaplastic large cell lymphoma. Cell Reports Medicine, 5(101472). DOI: https://doi.org/10.1016%2Fj.xcrm.2024.101472
About The Author
Dana-Farber Cancer Institute
Professor of Pediatrics
Harvard Medical School
Boston, Mass.
A. Thomas Look, M.D., is a Professor of Pediatrics at Harvard Medical School and a member of the Department of Pediatric Oncology at the Dana-Farber Cancer Institute. Look received his M.D. degree and postgraduate training in Pediatrics from the University of Michigan and his fellowship training in Pediatric Oncology at St. Jude Children’s Research Hospital, where he advanced over twenty years to become Chair of the Experimental Oncology Department and Professor of Pediatrics at the University of Tennessee College of Medicine. He moved from St. Jude Children’s Research Hospital to Dana-Farber Cancer Institute and Harvard Medical School in 1999 specifically to establish a research program in the zebrafish as a model of human cancer.
Over the past four decades, Look has published 390 peer-reviewed papers addressing the molecular basis of malignant transformation, aberrant proliferation and apoptosis in cancer cells and the application of molecular genetic findings to improve the treatment of malignancies of children and adults, particularly T-cell acute leukemia, neuroblastoma and myelodysplastic syndrome.
Look has conducted genetic studies aimed at the identification of novel targets for cancer therapy, and he is now internationally recognized as a leader in this field. His group discovered the anaplastic lymphoma tyrosine kinase receptor (ALK) gene in 1994. Look went on to show that leukemic T cells harbor “core” transcriptional networks that closely resemble those controlling the pluripotency of embryonic stem cells, dramatically changing the perception of T-ALL as a molecularly uniform disease to one comprising numerous distinct subtypes. More recently, Look and his colleagues showed that acquired mutations in a key enhancer region upstream of the TAL1 oncogene creates novel binding sites for the MYB transcription factor. MYB binding promotes binding of other members of the TAL1 complex and initiates a super-enhancer upstream of the TAL1 oncogene, driving high levels of expression that culminate in T-ALL. This discovery provides a conceptual framework for understanding the genetic events that transform human thymocytes and for developing effective strategies of individualized therapy.
In addition, his laboratory developed the first zebrafish transgenic models of T-cell acute lymphoblastic leukemia and childhood neuroblastoma, opening up the opportunity to apply the powerful genetic and chemical biology technology applicable to the zebrafish model to identify new molecular targets and small molecule drugs for therapy in these childhood cancers. His laboratory has also developed the first zebrafish models of myelodysplastic syndrome and clonal hematopoiesis due to loss of TET2, ASXL1 and DNMT3A, which he is using to identify drugs that selectively target mutant hematopoietic stem and progenitor cells, while sparing normal hematopoiesis.
