Protein synthesis, the most energetically demanding processes in our cells, is a central hallmark of cancer when dysregulated. A research team led by Dr Cristian Bellodi at Lund University has now discovered a key role for RNA modification in directing the production of proteins essential for the function of human stem and leukemic cells.
These new findings are based on years of hard work by the Bellodi laboratory and reveal a key mechanism in the development of leukemia, uncovering how regulation of an essential and naturally occurring, type of of RNA modification, known as pseudouridine, impacts fundamental biological processes involved in development and tumor formation.
The team has built on this fundamental discovery to illuminate the mechanism by which pseudouridine-modified small non-protein-coding (nc)RNA molecules, also known as miniTOGs (mTOGs), regulate the amount of proteins produced by blood-forming (hematopoietic) stem cells, and provide new insights regarding whether the regulation of this pathway is important for human disease, with a focus on myelodysplastic syndromes (MDS).
MDS affect just over 500 people, each year, in Sweden, and even more around the world. MDS is a group of chronic blood disorders, most common among older adults, where the formation of mature blood cells does not function normally due to HSC dysfunction. Notably, it has been reported that high protein synthesis rates in specific populations of HSCs can fuel the development of leukemia in some patients with MDS.
Using combinations of cutting-edge technologies, researchers revealed that mTOGs control production of critical components needed to regulate protein synthesis in stem cells, creating a “failsafe” mechanism during their development. Important to note is that this regulatory process of protein production is often “hijacked” in cancer cells.
“Our basic findings demonstrate that mTOGs precisely “tune” the amount of protein being produced in stem cells. Strikingly, protein synthesis is also the “Achilles’ heel” of cancer cells, opening new avenues to explore the role of mTOG in human disease.” – Dr Sowndarya Muthukumar, one of the three first co-authors of the study together with Nicola Guzzi and Maciej Cieśla.
Armed with this knowledge, the team, led by Dr. Bellodi, joined forces with Dr. Marios Dimitrou, and Professor Eva Hellström-Lindberg at the Center for Hematology and Regenerative Medicine at the Karolinska Institutet in Stockholm, and other leading experts in MDS genetics in Italy and Japan. Their aim? To investigate mTOG function in the HSCs of patients with MDS and understand their ability to predict a patients progression to aggressive forms of leukemia.
“It was like going to a treasure land as we could directly delve into the clinical implications of our mechanistic findings using one-of-a-kind patient-derived stem cell populations, collected over a 10 year period,” explained Sowndarya Muthukumar.
Notably, researchers found that patients with MDS, who had low levels of mTOGs, had a poor prognosis and a higher risk of developing lethal forms of leukemia. They also found that lower amounts of mTOGs in the bone marrow of these MDS patients correlated with elevated protein synthesis rates and a higher number of leukemic stem cells.
“Given that protein synthesis is abnormally increased in MDS HSCs, during leukemia development, we asked whether mTOGs could target the protein synthesis ‘machinery’ in these pre-leukemic stem cell populations,” comments Cristian Bellodi.
As it turns out, treatment with synthetic mTOGs restored protein synthesis, normalizing healthy blood cell production in these patients. Further benefits were revealed following transplantation of MDS patient HSCs in experimental models.
“Collectively, our results suggest that mTOGs may provide a new means to understand the molecular cause driving the development of leukemia among patients with MDS. Even more exciting is the possible transformative approach for using modified RNA molecules as a therapeutic tool to eliminate specific populations of cancer-initiating cells,” noted Cristian Bellodi.
Overall, the study defines an entirely new RNA epigenetic pathway in human disease with significant clinical and therapeutic implications, as pseudouridine is also widely employed in mRNA vaccines. “This work reveals many novel facets that may serve as a springboard for innovative research projects and exciting discoveries in the years to come,” concluded Cristian Bellodi.