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 Dana-Farber Cancer Institute and Boston Children's Hospital have elucidated crucial mechanisms in ALCL pathology, providing a potential avenue for targeted therapies. Their findings, published in Cell Reports Medicine, reveal how STAT3, a key signaling protein, integrates with central transcriptional regulators to maintain 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 such as 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 usually driven by chromosomal rearrangements that activate the ALK tyrosine kinase or by other mutations that lead to continued activation of the JAK-STAT signaling pathway. Professor Look and his team discovered that in ALCL cells, activated STAT3 binds to other key transcription factors (BATF3, IRF4 and IKZF1) to form a central regulatory circuit (CRC) that promotes cell survival and proliferation. cancerous. “Our research demonstrated that ALCL cells are highly dependent on a small group of central regulatory transcription factors. Addressing these dependencies opens new avenues for therapeutic intervention,” said Dr. Zimmerman.
The team used ChIP-seq chromatin immunoprecipitation sequencing to map enhancer regions in ALCL cells, identifying a conserved set of super-enhancers associated with genes such as BATF3, IRF4 and IKZF1. These regions were highly enriched in H3K27ac, a histone modification characteristic of active enhancers, underscoring the role of transcription factors encoded by these genes in driving high levels of expression of an extended genetic program critical for the malignant phenotype. . Furthermore, genome-wide occupancy analysis showed that STAT3, after activation by ALK kinase, collaborates with these CRC transcription factors into super-enhancers, ensuring sustained expression of 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 critical role as a signal-responsive transcription factor. Once activated by tyrosine kinase signaling, STAT3 works in concert with CRC to regulate the expression of MYC, a well-known oncogene. “Our findings suggest that STAT3, together with CRC transcription factors, drives the oncogenic gene expression program in ALCL,” Dr. Abraham said.
Professor Look emphasized the long-term importance of his 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 The current article 30 years later, provides a key mechanism of transformation in a large percentage of ALCLs that harbor the t(2;5) chromosomal translocation.
In functional assays, the researchers demonstrated that disruption of any individual CRC component significantly impaired the growth and viability of ALCL cells. In particular, pharmacological degradation of IKZF1 led to a reduction in cell growth, emphasizing its essential role in the positive regulation of CRC, which is essential for the proliferation and survival of ALCL cells. Furthermore, the team showed that STAT3 inhibitors, such as STAT3-IN-3 and Stattic, effectively reduced the viability of ALCL cells, and their combination with IKZF1 degraders produced even more substantial antitumor effects.
One of the critical insights from the study was the interaction between STAT3 and MYC. Using ChIP-seq, the researchers discovered that STAT3 binds to the super-enhancer regulatory regions of the MYC gene, producing high levels of the MYC protein, which then collaborates with CRC transcription factors to maintain high levels of MYC expression. This interaction 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-targeting therapies,” Professor Look added.
In conclusion, this study sheds light on the intricate regulatory networks that sustain ALCL and identifies STAT3 as a linchpin in the oncogenic process. The collaborative efforts of the research team have paved the way for new therapeutic strategies targeting the interconnected transcriptional dependencies in ALCL. As Professor Look said: “Our work provides fundamental insights into the molecular biology of ALCL, which will guide future research towards more effective treatments.”
Magazine reference
Prutsch, N., He, S., Berezovskaya, A., Durbin, AD, Dharia, NV, Maher, KA,… and Look, AT (2024). STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuit 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 Mira, MD, is a Professor of Pediatrics at Harvard Medical School and a member of the Department of Pediatric Oncology at Dana-Farber Cancer Institute. Look received his medical 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 Chairman of the Department of Experimental Oncology and Professor of Pediatrics at the University of Tennessee College of Medicine. He moved from St. Jude Children's Research Hospital to the Dana-Farber Cancer Institute and Harvard Medical School in 1999 specifically to establish a research program in zebrafish as a model of human cancer.
Over the past four decades, Look has published 390 peer-reviewed articles 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 in children and adults, particularly T-cell acute leukemia, neuroblastoma and myelodysplastic syndrome.
Look has conducted genetic studies aimed at identifying new targets for cancer therapy and is now internationally recognized as a leader in this field. His group discovered the anaplastic lymphoma receptor tyrosine kinase (ALK) gene in 1994. Look went on to demonstrate that leukemic T cells harbor “core” transcriptional networks that closely resemble those that control the pluripotency of embryonic stem cells, changing dramatically changed the perception of T-cell ALL as a molecularly uniform disease to one comprising numerous distinct subtypes. More recently, Look and his colleagues demonstrated that acquired mutations in a key enhancer region upstream of the TAL1 oncogene create new binding sites for the MYB transcription factor. Binding of MYB promotes binding of other members of the TAL1 complex and initiates a super-enhancer upstream of the TAL1 oncogene, resulting in high levels of expression culminating in T-ALL. This discovery provides a conceptual framework to understand the genetic events that transform human thymocytes and to develop effective individualized therapy strategies.
Additionally, his laboratory developed the first transgenic zebrafish models of T-cell acute lymphoblastic leukemia and childhood neuroblastoma, opening the opportunity to apply the powerful genetic and chemical biology technology applicable to the zebrafish model to identify new molecular targets and drugs of small molecule 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 cells and progenitors, while preserving normal hematopoiesis.
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