A partially typed large cell lymphoma (ALCL) of aggressive CD30+ T-cell lymphoma presents a huge challenge in oncology due to its complex genetic basis and resistance to conventional therapies. Researchers led by Professor Thomas examined the Dana-Farber Cancer Institute and Boston Children’s Hospital elucidate the key mechanisms of ALCL pathology for targeted Therapy provides potential avenues. Their findings, published in cellular reporter medicine, reveal how a key signaling protein, STAT3, integrates with core transcriptional regulators to maintain the malignant state of ALCL.
The research team, including Dr. Nicole Prutsch, Dr. Brian Abraham, Dr. Mark Zimmerman, and colleagues, began the study to understand the exact role of STAT3 in ALCL. Their collaborative efforts cover institutions including St. Jude Children’s Research Hospital, the University of Cambridge, the Medical University of Vienna, and the Dana Farber Cancer Institute. The study was published in the peer-reviewed journal Cell Reporting Medicine.
ALCL often results in continuous activation of the JAK-STAT signaling pathway by chromosomal rearrangements or other mutations that activate ALK tyrosine kinase. Professor Look and his team found that in ALCL cells, the role STAT3 binds to other key transcription factors (BATF3, IRF4 and IKZF1) to form a core regulatory circuit (CRC) that promotes cancer cell survival and proliferation. “Our study shows that ALCL cells are highly dependent on a small number of core regulatory transcription factors. Targeting these dependencies opens new avenues for therapeutic interventions,” said Dr. Zimmerman.
The team used chromatin immunoprecipitation sequencing (CHIP-SEQ) to map enhancer regions in ALCL cells, thereby identifying a conserved set of superenhancers associated with the BATF3, IRF4 and IKZF1 genes. These regions are highly enriched with H3K27AC, a histone modification feature of active enhancers, highlighting the role of these genes in promoting high-level expression of extended gene programs that are critical to the malignant phenotype. Furthermore, genome-wide occupancy analysis showed that STAT3 cooperated with these CRC transcription factors of the superenhancer after ALK kinase activation to ensure sustained expression of oncogenes.
This study highlights that STAT3 plays a key role as a signal-responsive transcription factor despite not meeting typical criteria for CRC components due to the absence of superenhancing agent expression. Once activated by tyrosine kinase signaling, STAT3 acts simultaneously with CRC to regulate the expression of MYC, a well-known oncogene. “Our findings suggest that STAT3, together with CRC transcription factors, drives oncogene expression programs in ALCL,” noted Dr. Abraham.
Professor Look highlighted the long-term significance of their research, noting: “My lab discovered the ALK gene and the NPM-Alk fusion gene in 1994, which provides activated tyrosine kinase signaling that activates STAT3, as we As reported in our study, the gene activates STAT3. Thirty years later, the current paper provides a key mechanism for transformation in most ALCLs containing T(2;5) Chormosomal translocations.”
In functional assays, the researchers showed that any single component that destroys CRC significantly impairs the growth and viability of ALCL cells. In particular, pharmacological degradation of IKZF1 leads to reduced cell growth, highlighting its important role in upregulating CRC, which is crucial for ALCL cell proliferation and survival. Furthermore, the team showed that STAT3 inhibitors such as STAT3-IN-3 and Stattic effectively reduced the viability of ALCL cells and that binding with IKZF1 degraders produced a more substantial anti-tumor effect.
One of the key insights from this study is the interaction between STAT3 and MYC. By using CHIP-SEQ, the researchers found that STAT3 binds to the superenhancer-regulatory region of the MYC gene, which produces high levels of MYC protein, which then cooperates with CRC transcription factors to maintain high MYC expression levels. This interaction emphasizes the therapeutic potential of targeting STAT3 in ALCL, especially in the case of anti-ALK inhibitors. “By demonstrating that STAT3 activation is necessary for MYC expression and ALCL cell survival, we provide a strong reason for the development of STAT3 targeted therapies,” Professor Look added.
In summary, this study elucidates the complex regulatory network that maintains ALCL and recognizes STAT3 as a linchpin during oncogenic processes. The collaborative efforts of the research team pave the way for novel therapeutic strategies targeting interconnected transcription dependence in ALCL. As the professor put it, “Our work provides critical insights into the molecular biology of ALCL, thereby guiding future research for more effective treatments.”
Journal Reference
Prutsch, N., He, S., Berezovskaya, A., Durbin, AD, Dharia, NV, Maher, Ka,…&take,&Look, to,&Look, at (2024). STAT3 couples activated tyrosine kinase signaling and oncogenic core transcriptional regulatory circuits for degenerative large cell lymphoma. Cell Report Drugs, 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, Massachusetts.
A. What Thomas looks likeMD, 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 a degree and graduate training in pediatrics from the University of Michigan and a fellowship in pediatric oncology at St. Jude Children’s Research Hospital, where he was promoted for more than 20 years to become chair of the Department of Experimental Oncology and chair of the professor of pediatrics. University of Tennessee School of Medicine. He moved from St. Jude Children’s Research Hospital to Dana-Farber Cancer Institute and Harvard Medical School in 1999 to establish a research program specifically in zebrafish as a model for human cancer.
Over the past four decades, Look has published 390 peer-reviewed papers covering the molecular basis of malignant transformation, abnormal proliferation and apoptosis in cancer cells, as well as the application of molecular genetic discovery to improve malignancy in children and adults Treatment of tumors for acute leukemia, neuroblastoma and myeloproliferative syndrome.
Look has conducted genetic research aimed at identifying new targets for cancer therapeutic targets, and he is now considered internationally as a leader in the field. His group discovered tumor lymphoma with the breast cancer kinase receptor (ALK) gene in 1994. It still appears that leukemia T cells have a “core” transcriptional network that closely resembles people who control embryonic stem cells’ versatility, greatly altering T-T-T-T-T-T-T-T-T-T-T-T-T-T-T-T-T-T-T-T-T-T-T-T-T-Sensing. All of these are molecularly homogeneous diseases, including many different subtypes. Recently, Look and colleagues have shown that mutations obtained in key enhancer regions upstream of the TAL1 oncogene create novel binding site for MYB transcription factors. MYB binding facilitates binding of other members of the TAL1 complex and initiates superenhancing agents upstream of the TAL1 oncogene, promoting high levels of expression, and ultimately orgasm in T-ALL. This finding provides a conceptual framework for understanding genetic events that alter human thymocytes and develop effective strategies for personalized therapies.
In addition, his lab developed the first zebrafish transgenic model for T-cell acute lymphocytic leukemia and pediatric neuroblastoma, providing opportunities for applying powerful genetic and chemical biology techniques suitable for zebrafish models to identify New molecular targets and small molecule drugs to identify treatments for these childhood cancers in zebrafish models. Due to the loss of TET2, ASXL1 and DNMT3A, his lab also developed the first zebrafish models for bone marrow production syndrome and cloned hematopoiesis, which he used to identify selectively targeted mutant hematopoietic stem cells and progenitor cells. Drugs, and at the same time, exceed normal hematoma.
