The evolution of leukemia is already written from its beginning

The results of a study aimed at identifying the mechanisms that determine the evolution of leukemia, relapses after treatment and, in some patients, transformation to a very aggressive lymphoma have been presented.

The study shows that the cells that cause relapse after treatment and that will lead to the transformation of leukemia into a very aggressive tumor can be detected – although in a very small quantity – at the beginning of the disease, that is, many years before complications become clinically manifest. The results of this work change the vision that was had of how leukemia progresses.

The study has been coordinated by Elías Campo, professor at the Faculty of Medicine and Health Sciences of the University of Barcelona (UB), director of the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) in Barcelona and head of the Research Group of Molecular Pathology in Lymphoid Neoplasms and the group of the Cancer Network Biomedical Research Center (CIBERONC) in Spain, and Ferran Nadeu, postdoctoral researcher at IDIBAPS and CIBERONC. The first co-authors of the work are, in addition to Nadeu, Romina Royo, researcher at the Barcelona Supercomputing Center; Ramon Massoni-Badosa, researcher at the National Center for Genomic Analysis; Heribert Playa-Albinyana, IDIBAPS and CIBERONC researcher, and Beatriz Garcia-Torre, IDIBAPS researcher.

The Big Bang Theory of Cancer Evolution

Until now, it was believed that leukemia progressed because its cells evolved over time and became more aggressive tumors because their genome progressively acquired alterations in their genome that made them more resistant to treatment. The new work shows that some of the leukemia cells have already acquired these alterations at the beginning of the disease, but they are found in very small quantities. During the evolution of the disease, these more malignant cells will prosper and, progressively, will be selected to cause clinical complications many years later. “It is as if the leukemia stem cell had engendered many daughter seeds since the beginning of the disease, each one of them with different alterations that will allow them to grow in the future when the conditions are more suitable for it,” says Elías Campo.

These observations confirm the so-called big bang theory of cancer evolution, which proposes that the original malignant cell multiplies rapidly into a large number of very diverse daughter cells with multiple alterations that give rise to future complications due to a selection process of the cells. more adapted. “This new view of the disease opens the door to developing highly sensitive diagnostic tests that allow us to detect and treat these malignant seeds many years before they can grow uncontrollably,” explains Elías Campo.

Researchers Ferran Nadeu and Elías Campo have coordinated the investigation. (Photo: UB)

The transformation of chronic lymphatic leukemia into a more aggressive tumor

Chronic lymphatic leukemia is the most common leukemia in the Western world, with an incidence of about 5 cases per 100,000 inhabitants each year. It is usually indolent, but it can evolve into a very aggressive large B-cell lymphoma with a median survival of less than one year. This tumor transformation occurs in approximately 5-10% of patients.

For the new study, the researchers set out to examine in depth the alterations that determine the progression of leukemia using blood samples obtained at different times of the disease. In the study, new highly sensitive techniques were applied, including individual genome sequencing of thousands of tumor cells at each time point in their evolution. Tumor samples were collected from 19 patients with chronic lymphocytic leukemia at diagnosis, at relapses after different treatments and until the final moment of transformation to aggressive lymphoma. Thus, the study covers up to nineteen years after the onset of the disease.

In the study, the genomic alterations that determine progression were identified and, surprisingly, they found that some (few) cells already had these alterations at the earliest stage of the disease. In addition, in the metabolism of these more aggressive cells, they identified alterations that, fortunately, seem to be a weakness, an Achilles’ heel that could be used to treat or prevent these complications.

“We have seen that if we treat the transformed cells with a drug that blocks this metabolism, we markedly reduce their growth”, comments Ferran Nadeu. This drug is already being tested in clinical trials in patients with other types of leukemia and solid tumors, and the current study suggests that it could also be used in chronic lymphatic leukemia.

“This research illustrates how an aggressive transformation occurs in the context of indolent cancer, a phenomenon that could be explored beyond this type of leukemia,” says Elías Campo. “The study shows that single-cell DNA and RNA sequencing is a necessary tool to delve into the biology of cancer and that it will help us diagnose and find new treatments to deal with the disease,” he concludes.

The study is titled “Detection of early seeding of Richter transformation in chronic lymphocytic leukemia.” And it has been published in the academic journal Nature Medicine. (Source: UB)