The progression of leukaemia is already written from its onset at the time of diagnosis

Researchers at IDIBAPS-Clínic Barcelona have coordinated a study to identify the mechanisms that determine the evolution of leukaemia, its relapses after treatment and its transformation into a very aggressive lymphoma in the final stage of some patients.

The study, published in the journal Nature Medicine, and financed with a grant of one million euros from the CaixaResearch call for health research, shows that the cells that cause relapse after treatment and that will lead to the transformation of leukaemia into a very aggressive tumour can already be detected in very small quantities at the beginning of the disease many years before these complications become clinically apparent. The results of this work change the previously held view of how leukaemia progresses.

The article has been coordinated by Dr. Elías Campo, director of IDIBAPS, head of the Molecular Pathology in Lymphoid Neoplasms group and group leader of CIBERONC, and Dr. Ferran Nadeu, post-doctoral researcher at IDIBAPS and CIBERONC. The first co-authors of the paper are, in addition to Ferran Nadeu, Romina Royo, researcher at the Barcelona Supercomputing Center - Centro Nacional de Supercomputación (BSC-CNS); Ramon Massoni-Badosa, researcher at the Centro Nacional de Análisis Genómico (CNAG-CRG); Heribert Playa-Albinyana, researcher at IDIBAPS and CIBERONC; and Beatriz Garcia-Torre, researcher at IDIBAPS.

Until now it was believed that leukaemia progressed because its cells evolved over time and transformed into more aggressive tumours because they progressively acquired alterations in their genome that made them more resistant to treatment. The new work shows that some leukaemia cells have already acquired these alterations at the onset of the disease, but they are found in very small quantities. As the disease progresses, these more malignant cells will increase and progressively select for clinical complications many years after the onset of the disease. "It is as if the leukaemia stem cell had sired many, many daughter seeds from the onset of the disease, each with different alterations that will allow them to grow in the future when conditions are more suitable," says Elías Campo.

These observations confirm the so-called "Big Bang" theory of cancer evolution, which proposes that the original malignant cell rapidly multiplies into a large number of very diverse daughter cells with multiple alterations that give rise to future complications through a process of selection of the most adapted ones. "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 out of control," explains Elías Campo.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the Western world, with an incidence of about 5 cases per 100,000 inhabitants per year. It is usually indolent, but can progress to a very aggressive large B-cell lymphoma with a median survival of less than one year. This tumour transformation occurs in approximately 5-10% of patients.

For the study in Nature Medicine, the researchers set out to study in depth the alterations that determine the progression of leukaemia using blood samples obtained at different times of the disease with new, highly sensitive techniques that include individual genome sequencing of thousands of tumour cells at each stage of progression. Tumour samples were collected from 19 CLL patients at diagnosis, at relapse after different treatments and until the final time of transformation to aggressive lymphoma covering up to 19 years after disease onset.

In the study, they identified genomic alterations that determine progression and, surprisingly, found that a few cells at the earliest stage of the disease already had these alterations.

In addition, they also identified alterations in the metabolism of these more aggressive cells that, fortunately, appear to be a weakness of these cells, an Achilles heel that could be exploited 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," says Ferran Nadeu. This drug is already being tested in clinical trials in patients with other types of leukaemia and solid tumours, and the current study suggests that it could also be used in chronic lymphocytic leukaemia.

"This research illustrates how aggressive transformation occurs in the context of indolent cancer, a phenomenon that could be explored beyond this type of leukaemia," says Elías Campo. "The study demonstrates that DNA and single-cell RNA sequencing is a necessary tool for further study of cancer biology and will help us to diagnose and find new treatments to tackle the disease," he concludes.

The study was made possible thanks to funding from the "la Caixa" Foundation and the European Research Council (ERC) to Dr. Elías Campo and from the American Association for Cancer Research (AACR), the European Haematology Association (EHA) and the Lady Tata Memorial Trust to Dr. Ferran Nadeu.