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New insights and pioneering work in targeted therapy against blood cancer

17.04.2024: Leukemias are caused by transformation of immune cells and are the most common form of cancer in children, but also occur in older people. Despite significant improvements in diagnosis and treatment options over the last few decades, some types of leukemia are still considered incurable. In addition, relapses and toxic side effects of chemotherapy still pose major challenges for clinicians treating patients and worsen quality of life and shorten patients' lives. T-cell acute lymphoblastic leukemia (T-ALL) results from the transformation of immature T cells. T-ALL patients have have a worse prognosis than other acute blood cancers, partly due to a lack of understanding of the underlying signaling pathways in the cancer cells and limited targeted therapy options.

The research team led by Richard Moriggl at the University of Veterinary Medicine, Vienna has now been able to elucidate disease mechanisms that could make a decisive contribution to the development of new treatment options for T-ALL. Using a novel mouse model, the researchers were able to show for the first time that the DNA-regulating protein ("transcription factor") STAT5B can trigger T-ALL in a mutated form. Due to the mutation, which is frequently found in T-ALL patients, STAT5B is in a constitutively active state and thus fuels the production of target proteins of STAT5B, which promote cell division and thus cancer growth. Some of these proteins are normally involved in the immune response of mature T cells, e.g. in response to viral or bacterial infections. These activated T cells are normally deactivated after the infection has been overcome to avoid an overreaction of the immune system.

The first author of the study now published in the Journal of Clinical Investigation, Tobias Suske, who is working with the biotech company RIANA Therapeutics on active substances against STAT5, found that the permanent activation of STAT5B suspends this mechanism. This allows the immature T cells to proliferate, which ultimately leads to the development of leukemia. Two different approaches for therapies were tested within the study through pilot experiments in mouse model systems: Agents targeting STAT5B were able to drastically reduce cancer growth of human T-ALL cells in the mice. Similar effects were achieved by an agent against one of the STAT5B target proteins that acts enzymatically and turns on other signaling cascades, ZAP70. Targeted inhibition of ZAP70 has the distinct advantage of providing a drug that is already approved for the treatment of other hematologic diseases but has never been tested in T-ALL. In contrast, the STAT5B compound still requires further development.

However, the STAT5B mutation has been found over the last decade not only in T-ALL but also in other T-cell leukemia/lymphoma patients, and as is so often the case with cancer, the exact reasons for this multifaceted occurrence are still unclear. However, this means that the knowledge gained can also be transferred to these diseases, which may lead to new or improved therapies and require further clinical trials.



Graphical abstract (Credit: Vetmeduni)

The article "Hyperactive STAT5 Hijacks T-Cell Receptor Signaling and Drives Immature T-Cell Acute Lymphoblastic Leukemia" was published in The Journal of Clinical Investigation.

Scientific article