The BSC participates in a study that changes the view of the evolution of leukemia

07 October 2022

The research concludes that the progression of the disease is already written right from the start, which opens the door to early diagnosis and offers new treatment strategies.

“We have identified the presence of a small number of cells that caused the transformation of chronic lymphocytic leukemia into a very aggressive lymphoma, up to 19 years before its manifestation, identifying a vulnerability that could be used therapeutically," says BSC researcher Romina Royo

Researchers from the Barcelona Supercomputing Center - Centro Nacional de Supercomputación (BSC-CNS) have participated in a study coordinated by IDIBAPS-Clínic Barcelona-UB to identify the mechanisms that determine the evolution of leukemia, relapses following treatment, and its transformation into a very aggressive lymphoma in the final phase for some patients.

The study, published in the journal Nature Medicine and financed with a grant from the CaixaResearch call for health research of one million euros, shows that cells that cause post-treatment relapse and that give rise to the transformation of leukemia into a very aggressive tumor can already be detected in a very small quantity at the start of the disease, many years before these complications reveal themselves clinically. The results of this work change the view held to date on how leukemia progresses.

BSC researcher Romina Royo has co-authored the study, which has been coordinated by Elías Campo, director of IDIBAPS, and Ferran Nadeu, researcher at IDIBAPS and the CIBERONC. Ramon Massoni-Badosa (CNAG-CRG), Heribert Playa-Albinyana (IDIBAPS) y Beatriz Garcia-Torre (IDIBAPS) have also been co-authors of the study.

The Big Bang theory of cancer evolution

Until now it was believed that leukemia progressed because its cells evolved over the course of time and transformed into more aggressive tumors because they acquired alterations to their genome in a progressive manner that made them more resistant to treatments. This new study shows that some of the leukemia cells have already acquired these alterations right at the start of the disease, but they are only found in very small quantities. During the evolution of the disease, these more malignant cells will grow and progressively be selected, giving clinical complications many years after disease onset.

These observations confirm the so-called “Big Bang” theory of cancer evolution that proposes that the original malignant cell rapidly multiplies into many very diverse daughter cells with numerous alterations that give rise to future complications through a selection process of those best adapted.

The transformation of chronic lymphatic leukemia into a more aggressive tumor

Chronic lymphatic leukemia (CLL) is the most frequent leukemia in the western world, with a frequency of some 5 cases per 100,000 inhabitants per year. It is usually slow-growing but can evolve towards a very aggressive large B-cell lymphoma that has an average survival rate of below one year. This tumoral transformation occurs in approximately 5-10% of patients.

"In this study we have seen how CLL, from its early stages, presents a great heterogeneity that contains the seeds that will be able to give rise to the different relapses of the disease and its transformation towards more aggressive lymphomas. Accordingly, we have identified the presence of a small number of cells that will lead to the transformation of CLL into a very aggressive lymphoma, up to 19 years before its manifestation, and we have identified a vulnerability of these cells that could be used therapeutically," says BSC researcher Romina Royo, one of the main co-authors of the study.

In the study, genomic alterations that determine progression were identified and, surprisingly, it was found that a few cells at the earliest stage of the disease already had these alterations. The scanning of the complete tumor genome of 19 patients, carried out on the BSC's MareNostrum 4 supercomputer, has made it possible to investigate not only the mutations or changes in the tumor's DNA, but also the mutational processes that had given rise to these changes and their evolution.

"These analyses pointed to the presence of transformed cells already present at the time of CLL diagnosis, years before its spread. We corroborated this fact with other more sensitive techniques such as single cell sequencing," Royo adds.

Tumor vulnerability could be used therapeutically

Furthermore, they also identified alterations in the metabolism of these more aggressive cells that, fortunately, seem to be a weakness for them, an Achilles’ heel that could be taken advantage of to treat or prevent these complications. "We have also identified a vulnerability of these tumors that could be used for their treatment, and we have shown how the proliferation of these transformed cells can be reduced by applying a drug that acts on this weak point," says Royo. 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 within the context of a slow-growing cancer, a phenomenon that could be explored beyond this type of leukemia”, notes Elías Campo. “The study shows that single-cell RNA and DNA sequencing is a necessary tool for in-depth analysis of the biology of cancer and it will help us to diagnose and find new treatments for tackling the disease”, he concludes.