St. Anna Children’s Cancer Research Institute (CCRI) is investigating how endoplasmic reticulum is linked to a newly discovered immunodeficiency

St. Anna Children’s Cancer Research Institute investigates the control center for maintaining cell fitness

The endoplasmic reticulum in human cells is the topic of a current research project at St Anna Children’s Cancer Research Institute. This highly complex network of membrane structures is responsible for the production of the body’s own proteins and for their correct folding; important reactions for maintaining cell fitness are also coordinated here.

Genetic predispositions lead to tumors much more frequently in children than in adults. At least ten per cent of all childhood cancers develop in this way. Congenital immunodeficiencies, for example, can favor the development of tumors because cancer cells have a much easier time with a poorly functioning immune defense than under normal circumstances. This is why immunology is a central component of modern pediatric cancer research.

With the support of the Austrian Science Fund FWF, research is now being conducted on an innate immune defect that negatively impacts the function of the endoplasmic reticulum.

The team is led by Senior Postdoc Michael Kraakman and Kaan Boztug, MD, Scientific Director of St. Anna Children’s Cancer Research Institute.

The scientists have identified four patients with this defect in their immunity: These four children – one has since died – have a mutation in the gene involved in protein folding and protein degradation. Both are essential for the health of the cell: protein folding is the process by which proteins obtain their three-dimensional structure and is the prerequisite for the flawless function of the protein. Protein degradation is crucial to make room for new, correctly folded proteins. Clinically, the immunodeficiency results in frequent infections in all four cases.

New Zealand expert at the St. Anna Children’s Cancer Research Institute

The immunologist Michael Kraakman, PhD originally from New Zealand and the head of the FWF project, studied at Monash University in Melbourne, Australia, among other places, before a postdoctoral degree took him to Columbia University in New York. Since 2019, he has been working at St. Anna Children’s Cancer Research Institute in the group of the Scientific Director Prof. Kaan Boztug, MD. The study in question was started back then with data from two siblings, one of whom was able to survive the disease thanks to a transplant.

It is now known that the gene mutation indirectly slows down the work of lymphocytes and T-cells by influencing the endoplasmic reticulum. This cell organelle provides proteins needed by the defense cells to respond quickly to invaders. However, for a proper immune response, these proteins must be correctly folded. Kraakman says: “If the protein produced fails to attain the correct three-dimensional shape, the cell must label it as misfolded and remove it.” If the cell were not to do so, misfolded proteins would accumulate within the cell, hindering the ongoing production of new proteins. Therefore, the removal of misfolded proteins is vital.

Kraakman emphasizes the “tumor predisposition of children” because the defense mechanisms against tumor cells do not work adequately in the case of innate immunodeficiencies. “This is why these newly discovered diseases play such an important role in pediatric cancer research,” he says. 

About the St. Anna Children’s Cancer Research Institute

The St. Anna Children’s Cancer Research Institute (CCRI) is an international and interdisciplinary research institution dedicated to advancing diagnostic, prognostic, and therapeutic strategies for the treatment of children and adolescents with cancer through innovative research. Incorporating the specific characteristics of childhood tumor diseases, dedicated research groups collaborate in the fields of tumor genomics and epigenomics, immunology, molecular biology, cell biology, bioinformatics, and clinical research. Their aim is to bridge the latest scientific and experimental knowledge with the clinical needs of physicians in order to significantly improve the well-being of young patients. For more information, visit www.ccri.at or www.kinderkrebsforschung.at.