Scientists at Heidelberg University Hospital, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and HI-STEM gGmbH* have discovered a new mechanism for the self-renewal of leukemia stem cells. The study results help to better understand the aggressive course of acute myeloid leukemia.
Almost all tissues in our body contain a small number of stem cells that can divide indefinitely and are also capable of forming a large number of different mature cell types. Some cancer cells also acquire this ability and are then called cancer- or leukemia stem cells (LSCs) in case of some blood cancers. The presence and frequency of LSCs make blood cancers particularly aggressive and resistant to therapies. A team of researchers from Heidelberg University Hospital (UKHD), the German Cancer Research Center (DKFZ) and the Stem Cell Institute HI-STEM is investigating the molecular mechanisms that make up these leukemic stem cells in acute myeloid leukemia (AML). AML is a particularly aggressive cancer of the hematopoietic system. About 50 percent of patients suffer from a relapse after therapy, which is very hard to control and caused by surviving leukemia stem cells.
In the scientific journal "Cancer Discovery", the scientists describe a completely new molecular mechanism that turns normal leukemia cells into the particularly dangerous leukemia stem cells.
RNA methylation controls self-renewal mechanism and makes leukemic cells aggressive
The Heidelberg team focused its work on the group of molecules known as ribosomal ribonucleic acids (rRNA). Together with other components, rRNA forms the "protein factories" of cells, the ribosomes. Here, all proteins required for cell function are assembled from their components. Earlier research in Müller-Tidow's team had suggested that certain chemical modifications (methylations) to rRNA may influence cancer development.
In their current study, the researchers first showed that AML stem cells carry highly specific and dynamically regulated methylation patterns on their rRNA molecules. They then transplanted human AML cells, which have been engineered to produce a key protein controlling this methylation process, into mice. This allowed them to functionally study the consequence of differential rRNA methylation in human leukemic cells in an in vivo setting. The data revealed that these methyl marks influence the type of proteins produced by the leukemia stem cells. Moreover, the ability to self-renew - the most important functional feature of aggressive leukemic stem cells - was also stimulated via this mechanism.
"Our work provides completely new insights into the molecular mechanisms that make leukemia stem cells so dangerous and that have been poorly understood since their discovery more than 20 years ago" explains Andreas Trumpp, Head of the Division "Stem Cells and Cancer" at DKFZ and Director of HI-STEM. Carsten Müller-Tidow, Medical Director of the Department of Hematology, Oncology and Rheumatology at the UKHD, reports: "We have known for a long time that methylation of the genetic material is an important control mechanism that regulates the aggressiveness of tumor cells. We have now been able to show for the first time that the methylation of rRNA molecules of cancer cells also has a significant influence on the course of the disease. We hope that, based on our results, we will be able to develop new therapeutic approaches in the future that will also destroy generally highly resistant leukemia stem cells and thus finally defeat leukemia."
Zhou F, Aroua N, Rohde C, et al. A dynamic rRNA ribomethylome drives stemness in acute myeloid leukemia. Cancer Discov 2022; https://pubmed.ncbi.nlm.nih.gov/36259929/
* The Heidelberg Institute for Stem Cell Research and Experimental Medicine (HI-STEM) gGmbH was founded in 2008 as a public-private partnership by the DKFZ and Dietmar Hopp Foundation.