Genetic events that could trigger leukemia in patients with a rare genetic disorder are deciphered

Two parallel and complementary investigations by the IDIBELL team led by Dr Alessandra Giorgetti have succeeded in recreating disease models of GATA2 deficiency, a rare genetic disorder that affects fewer than 1 million people worldwide. Thanks to these new models developed by Dr Giorgetti's team, there is now a clearer idea of the molecular process by which the haematopoietic stem cells of these patients become cancerous.

The studies reveal that the initial mutation in GATA2, an essential gene for the formation of blood cells, promotes premature ageing of blood stem cells and enables these cells to make and accumulate errors during cell division. In addition, the research team describes the implication of the genetic events that precipitate acute myeloid leukaemia in patients with GATA2 deficiency.

The research has been carried out with the collaboration of researchers from the Institut Germans Trias i Pujol (IGTP), Institut de Recerca Sant Joan de Déu (IRSJD), the Hospital del Mar Research Institute, and the Josep Carreras Leukaemia Research Institute (IJC), among others, and has been developed thanks to funding from La Marató, EHA, ERAPerMed and the Spanish Ministry of Science.

The starting point: the mutation in GATA2, a key gene in blood cells

The first study, published in Leukemia, focused on investigating the effect of the GATA2 mutation on blood stem cells. To do so, a new cell model was generated, introducing the GATA2 mutation through advanced gene editing techniques (CRISPR-Cas), with which it was verified that the mutated cells showed signs of ageing compared to healthy cells.

"GATA2 is a crucial gene for haematopoietic stem cells to maintain the normal production of blood cells. When its function is altered, the cells begin to fail: they lose the ability to divide, make mistakes in the process, and lose their regenerative capacity. In other words, their functional capacity is reduced, similarly to what happens in aged stem cells," explains Damià Romero Moya, first author of the study and postdoctoral researcher at IDIBELL.

The malignant acceleration: the impact of secondary mutations

However, the GATA2 mutation on its own is insufficient to reach the development of leukaemia. It is a predisposing factor, but secondary mutations are needed to initiate the progression of the disease and the leap towards myelodysplastic syndrome (MDS) or leukaemia.

In this second study, the team introduced into their cell model the secondary mutations most frequently found in patients, especially in two genes (SETBP1 and ASXL1), to determine their exact impact. "Mutations in GATA2 prepare fertile ground for genetic instability, but by themselves they do not trigger the cancerous process. They define a context in which additional mutations related to premalignant stages, which we have detected in patients, can more easily appear. The combination of SETBP1 and ASXL1 would act synergistically, collapsing the production of healthy blood cells and promoting leukemic transformation," explains Joan Pera, first author of the second study, recently published in Nature Communications, and predoctoral researcher at IDIBELL.

What the IDIBELL team concludes is that the combination of the three mutations results in a severe impairment of haematopoiesis and directs the natural history of the disease towards the brink of leukaemia. Among all three mutations, the main driver of malignisation appears to be SETBP1. Alterations in this gene have a dominant impact on the mutational landscape, modifying the three-dimensional structure of DNA and exposing it to potential damage.

Searching for a cure beyond stem cell transplantation

GATA2 deficiency is a rare genetic disorder, present from birth, that can have a wide range of clinical manifestations, from immunodeficiencies to deafness and a high probability of developing blood cancers throughout life. In fact, it has been estimated that 80% of individuals with this disorder suffer from myelodysplastic syndrome, a group of blood disorders of low malignant potential which, nevertheless, in 1 out of 3 cases can progress to a fast-growing cancer: acute myeloid leukaemia.

"In the two articles we have published, a model for the study of the most frequent paediatric haematological neoplasia predisposition syndrome, GATA2 deficiency, is described for the first time. In addition, possible mechanisms implicated in progression towards leukaemia associated with this genetic defect are identified. These advances open new avenues for more precise patient monitoring and for the development of future therapeutic strategies," explains Dr Albert Català, from the Institut de Recerca Sant Joan de Déu (IRSJD).

The cell models developed in the IDIBELL laboratories, which faithfully represent the mutations observed in paediatric patients with this disorder, not only allow it to be studied in detail but also become a platform on which to test different compounds and drugs that attempt to restore the functionality of the affected stem cells. "Currently, GATA2 deficiency is a disorder that can only be cured with a stem cell transplant. With the new models we have generated, we hope to make available to the scientific community a tool that helps develop therapeutic strategies that allow correcting the original mutation more easily," notes Dr Alessandra Giorgetti, director of both studies, head of the research group in Biology of Haematopoietic Stem Cells and Leukemogenesis at IDIBELL and professor at the UB.