Scientists discover how leukemia forms and evolves

An international team of researchers from the Cima University of Navarra and the University of Cambridge describe for the first time the genetic regulation mechanisms that favor the evolution of leukemia. In this study, the most exhaustive to date, they have analyzed the differences in the generation of healthy blood cells versus leukemic ones. Specifically, they have focused on characterizing the gene regulation mechanisms that cells use to decide when and to what extent a gene is activated or deactivated (gene expression). Studying this process is very important since gene regulation determines whether the identity that the cells will take is a healthy cell or a leukemic cell. 

Using cutting-edge technologies, researchers have revealed that leukemic cells corrupt fundamental gene regulation mechanisms that determine the identity of healthy cells, blocking their evolution into mature, healthy cells and facilitating tumor growth.

Leukemia is the second most prevalent blood cancer. According to the latest Globocan report, in 2020, there were an estimated 474,519 new cases of people diagnosed with leukemia in the world. This finding opens the door to developing new treatments for these cancer patients.

The prestigious scientific journal Nature Genetics published the results of this multicenter study in the latest issue. Researchers from the University of Salzburg (Austria) and the biotechnology company Relation Therapeutics (United Kingdom) have also collaborated. Several of its researchers belong to the Cancer Network Biomedical Research Center (CIBERONC) and the Health Research Institute of Navarra (IdiSNA). "la Caixa" Banking Foundation, the European Commission (Marie Skłodowska-Curie Actions) and, Cancer Research UK, Wellcome Trust, funded this project, among other institutions.

Delve into the origin of cell formation

The blood cell formation process(hematopoiesis) begins in hematopoietic stem cells, generating different types of blood cells (white blood cells, red blood cells, and platelets). Specifically, it is in chromatin (the mixture of DNA and proteins that makeup chromosomes) where the genetic regulation processes occur that give rise to the great variety of cell types in the blood. Two groups of proteins called chromatin factors and transcription factors are involved in these processes.

Transcription factors mark the specific genes to be activated in each cell type, and chromatin factors regulate the expression of these genes through changes in the biochemical structure of chromatin. In this way, the identity of the blood cells is determined. The deregulation of these processes triggers different blood cancers, leukemia being the second most common.

Until now, the role that chromatin factors played in determining cell identity was unclear. However, the team of Cima and Cambridge researchers has shown that chromatin factors are a crucial element in regulating cell identity. To do this, they used cutting-edge CRISPR and single-cell technologies. Julen Mendieta and Ainhoa ​​Goñi, the first authors of the study and researchers at Cima Hemato-Oncology Program, which is part of the Cancer Center Clínica Universidad de Navarra, explain that "thanks to the use of a technology that allows us to study individual cells, we have demonstrated the complexity of the processes that regulate cells, revealing a great diversity in the function of chromatin factors, as well as other functions shared with transcription factors."

Cellular corruption in leukemia

By studying the processes that regulate cell identity in leukemia, this international team has revealed how leukemic cells corrupt the normal functions of chromatin factors to block evolution towards healthy cell types and facilitate tumor growth. In their analysis, they observed that in this alteration, new complexes of transcription factors and chromatin factors exclusive to leukemic cells were formed. "As these complexes are specific to leukemia and are not necessary for normal hematopoiesis, they are an ideal target for a therapy that can deactivate them without causing any further harm to the patient, unlike current treatments such as chemotherapy, with high levels of toxicity," says David Lara Astiaso, a researcher at the Department of Hematology at the University of Cambridge and lead author of the study.

Professor Brian Huntly, head of the Department of Hematology at the University of Cambridge and co-leader of the study, highlights that "identifying a potential new therapeutic avenue for leukemia is especially important. For example, in acute myeloid leukemia, which is the most common in adults and very aggressive, only 15% of people diagnosed with this disease survive more than five years."