The CNIO discovers a link between a rare form of anemia and cancer

Researchers from the Tumour Suppression Group at the Spanish National Cancer Research Centre (CNIO), headed by Manuel Serrano, have discovered the molecular mechanisms that determine cancer predisposition in patients with Diamond-Blackfan anaemia (DBA). To achieve this, they have created the first animal model that recapitulates key characteristics of this type of anaemia in humans, including high cancer susceptibility. The finding, published in the journal Cell Reports, could potentially improve current treatments for this disease, which are effective in resolving the haematological disorders but not in preventing the greater predisposition to cancer.

DBA is a rare type of anaemia that affects 5 people per million. It is characterised by blood disorders, short stature and malformations in the heart, palate and hands. Previous observational studies had reported that around 20% of these patients develop various types of cancer during their first 46 years of life; in particular, lymphomas - tumours of the blood - but also solid tumours such as colon cancer, osteosarcoma and gynaecological cancers. Other studies had developed animal models that recapitulate the characteristics of this type of anaemia, but not the predisposition to cancer.

Now, CNIO researchers have achieved this by working on the RPL11 protein. They have discovered that mice with partial deficiency of RPL11 (i.e. one of the two copies of the gene is faulty) not only suffer from the incorrect generation and maturation of red blood cells (causing anaemia), but are also predisposed to lymphomagenesis - the development of lymphomas.

INFLUENCE ON THE 'GUARDIAN OF THE GENOME'

DBA patients display alterations in ribosomal proteins, those that belong to the ribosomes, the organelles within cells that are responsible for synthesising proteins. However, when other research groups generated animal models with mutations in some of these proteins, those animal models experienced haematological disorders that are typical of anaemia -- red blood cells are not produced or do not mature properly -- but cancer predisposition was not reported. CNIO researchers decided to work specifically on the ribosomal protein RPL11 to try to recapitulate this feature in their animal model, and they were successful.

Manuel Serrano, who has led the study, explains why they chose to focus on this protein: "Cells need the ribosomes to function properly in order to proliferate and grow; we knew that when something goes wrong in these organelles, RPL11 operates as a switch that activates the p53 gene to stop the cells from proliferating and forming tumours; this mechanism is called ribosomal stress. P53 is one of the main tumour suppressor genes identified to date, to the extent that its relevance in preventing cancer has led to it being named the guardian of the genome. This important function made us think that the protein could play a crucial role in the cancer predisposition observed in patients with DBA: if RPL11 is mutated, it loses the ability to activate p53 to prevent tumours caused by cellular damage."