Home Medizin Wissenschaftler entdecken vier Proteine, die die Identität des anaplastischen großzelligen Lymphoms bestimmen

Wissenschaftler entdecken vier Proteine, die die Identität des anaplastischen großzelligen Lymphoms bestimmen

von NFI Redaktion

Researchers from St. Jude Children’s Research Hospital and the Dana-Farber Cancer Institute have identified four proteins that determine the identity of anaplastic large cell lymphoma (ALCL), an aggressive form of cancer. These proteins include a core regulatory circuit (CRC) that surprisingly contains a misregulated signaling protein. Establishing the CRC for this lymphoma provides insights into potential vulnerabilities that could serve as future therapeutic targets. The results were published today in Cell Reports Medicine.

„It has long been known that mutations in signaling pathways drive oncogenic transformation and tumor progression,“ said senior co-author Mark Zimmerman, PhD, currently at Foghorn Therapeutics, formerly at Dana-Farber Cancer Institute and Boston Children’s Hospital. „Our new findings demonstrate a mechanistic link between the activation of faulty signaling pathways and the misregulated gene expression that is a hallmark of these tumor cells.“

Tumors and models of ALCL patients showed significant dysregulation of a protein called Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 is a signaling protein that integrates information from other proteins and acts as a transcription factor (a protein involved in regulating the copying of genetic information from DNA to messenger RNA).

„We found that dysregulation of the signaling protein STAT3 is crucial for enforcing the ALCL cancer identity. A healthy cell has a ‚board‘ comprised of a few dominant regulatory authorities, and STAT3 is ‘promoted’ from a department head to a full board member, with total rights and powers,“ said Brian J. Abraham, PhD, co-author, St. Jude Department of Computational Biology.

Among the genes it controls, STAT3 increases the expression of the MYC protein, which is known to be associated with cancer. Nearly every tested ALCL cell line showed either a mutation in STAT3 or in a protein that sends signals to STAT3, causing it to be always „on“ and controlling gene expression, promoting continuous cell growth through its targets.

The findings have implications for treatment, as there are already drugs targeting the STAT protein family and other proteins that transmit signals through STAT3.

Search for a Central Regulatory Circuit for all ALCL Subtypes

„Transcription factors and proteins that regulate oncogenic gene expression programs prove to be some of the most direct and effective targets for cancer therapy,“ said lead author Nicole Prutsch, PhD, Dana-Farber Cancer Institute and Boston Children’s Hospital. „STAT3 has already been a recognized transcription activator in ALCL, but our research has identified a central transcriptional regulatory circuit hijacked by STAT3 to drive genes essential for ALCL cell growth.“

STAT3 hijacks three transcription factors that make up the CRC: BATF3, IRF4, and IKZF1. All were expressed in high levels in ALCL cells, despite lacking cancer-driving mutations. They were also identified as potential vulnerabilities in the DepMap Consortium’s gene knockout studies. When the scientists reduced the expression of one of these proteins, it significantly reduced cancer cell growth, demonstrating the central importance of the CRC.

„This is the first central regulatory circuit identified for ALCL to our knowledge,“ said Abraham. Both major known molecular ALCL subtypes, ALK-positive and ALK-negative, rely on the same CRC, despite their differences in survival rates.

„ALCL represents a diverse group of T-cell lymphomas with varying clinical behaviors,“ said Prutsch. „While ALK-positive cases respond well to ALK inhibitors, ALK-negative ALCL is extremely aggressive and has limited targeted therapy options, highlighting the urgent need for new treatment strategies.“

To understand the differences between subtypes and identify potential vulnerabilities, the researchers mapped specific complexes of DNA and proteins called Super-Enhancers, which strongly influence gene expression. In cancer, Super-Enhancers may play a role in maintaining the identity of the cancer as a malignant disease.

The researchers found that Super-Enhancers, which differed in ALCLs, converged to highlight the same CRC in all ALCL tumors and models.

„The central regulatory circuit appears to be the same in all diseases that have historically been treated as different diseases,“ said Abraham. „Regardless of whether an ALCL cell is ALK-positive or ALK-negative, it relies on the expression and positive feedback of this circuit to remain ALCL.“

Potential Vulnerabilities Highlight Treatment Options

Understanding the central role of the CRC in this type of cancer has implications for treatment. There are already drugs targeting the STAT protein family and other proteins that send signals through STAT3. However, they have had limited success, especially in ALK-negative diseases. Understanding the CRC and its interaction with STAT3 could enable the development of new therapeutics and combination strategies.

„Our results demonstrate a significant relationship between the members of the central regulatory circuit and STAT3,“ said Prutsch. „This underscores the potential for therapies that target these connections, offering attractive options for developing new treatments for ALK-negative ALCL.“

The same methods used in the study could also provide a way to understand and identify vulnerabilities in other malignant diseases without clear driver mutations.

„Our discovery shows that leveraging the interplay between signal and transcriptional dependencies is a rational approach to developing new treatment strategies for a broad spectrum of cancers,“ said Zimmerman.

Authors and Funding

Other authors of the study include Shuning He, Alla Berezovskaya, and Kimberly Stegmaier from Dana-Farber Cancer Institute and Boston Children’s Hospital; Neekesh Dharia from Genentech; Jamie Matthews, Lucy Hare, and Suzanne Turner from the University of Cambridge, Addenbrooke’s Hospital; Lukas Kenner from Masaryk University; Olaf Merkel from Medical University Vienna; and Adam Durbin and Kelsey Maher from St. Jude.

The study was supported by grants from the National Institutes of Health (R35CA210064, R35CA210030, and K08CA245251), the Lymphoma Research Foundation, Julia’s Legacy of Hope St. Baldrick’s Foundation Fellowship, the National Institute for Cancer Research (Program EXCELES, ID Project No. LX22NPO5102), European Union – Next Generation, Cancer Research UK Cambridge Centre (CTRQQR-2021\100012), Alex’s Lemonade Stand Foundation, Charles A. King Trust, Claudia Adams Barr Foundation, and ALSAC, the fundraising and awareness organization of St. Jude.

Source:

St. Jude Children’s Research Hospital

Journal Reference:

Prutsch, N., et al. (2024) STAT3 links activated tyrosine kinase signaling to the oncogenic core transcriptional regulation circuit of anaplastic large cell lymphoma. Cell Reports Medicine. doi.org/10.1016/j.xcrm.2024.101472.

Related Posts

Adblock Detected

Please support us by disabling your AdBlocker extension from your browsers for our website.