A Clínic-IDIBAPS study shows how one tumour clone can gain an advantage over others in Waldenström macroglobulinaemia. The findings link genetic changes and immune-cell interactions to disease progression.
A small group of tumour cells can eventually take control of Waldenström macroglobulinaemia. They do so after gaining advantages over competing cell populations. Researchers from Clínic-IDIBAPS traced this process by analysing more than 130,000 individual cells from patients at different stages of the disease. The findings may help explain why some cases remain indolent while others progress and need treatment.
The study examined bone marrow and blood samples from people with IgM monoclonal gammopathy of undetermined significance (IgM MGUS), indolent Waldenström macroglobulinaemia and symptomatic disease. The results were published in HemaSphere. Carlos Fernández de Larrea, David F. Moreno and Ferran Nadeu coordinated the work within the Clínic Barcelona Comprehensive Cancer Centre and IDIBAPS.
The study was published in HemaSphere under DOI 10.1002/hem3.70456, documenting how clonal competition can shape the expansion of Waldenström macroglobulinaemia.
The change can be seen in the tumour's structure. Early-stage disease contains several B-cell clones living alongside one another. In more advanced Waldenström macroglobulinaemia, one dominant tumour clone usually takes over.
This points to biological competition rather than a single, uniform expansion from the beginning. Several cell populations coexist in the early stages. One of them can gain traits that improve its growth and survival. It then becomes the main driver of the disease. Clínic Barcelona described this clonal selection model as a central conclusion of the single-cell study.
The dominant cells showed more activity in genes and regulatory mechanisms linked to cell growth and survival. These molecular markers could help distinguish the clone that is gaining ground from other B cells. They may also clarify how the expansion takes place.
Waldenström macroglobulinaemia is classified separately under code C88.0 in the international disease classification. This distinction supports clinical separation of symptomatic WM from IgM MGUS and other plasma-cell or B-cell disorders. Clinical guidance also generally reserves treatment for significant symptoms or complications, rather than starting therapy during asymptomatic observation.
Genetic changes add another layer to the disease. Loss of part of chromosome 6 appeared more often in patients with higher-risk forms. This confirms an alteration previously linked to a less favourable clinical course. The analysis also confirmed characteristic mutations such as MYD88.
Some of these changes were already present in the early phases, before one cell population had become dominant. Genetic changes may therefore give selected clones an advantage without immediately producing the full clinical picture of symptomatic disease.
The tumour cells also interacted closely with their surroundings in the bone marrow. The strongest communication detected in the study was between dominant tumour cells and monocytes, which are immune cells involved in the body's response. The local immune environment is therefore part of the disease's development, rather than a passive backdrop.
Carlos Fernández de Larrea, David F. Moreno and Ferran Nadeu's team combined genomic, transcriptomic and epigenetic information at single-cell level. This made it possible to track the diversity present at the start. It also showed the biological advantages that later allow one clone to overtake the others.
The findings may improve patient classification and help shape future treatment strategies. The proposed markers and mechanisms still need to be tested in larger studies and independent cohorts. If the results are confirmed, single-cell profiling could help identify patients at greater risk of progressing to treatment and point to molecular targets for earlier intervention.
The study does not present a new therapy. Its main contribution is a clearer map of how the disease changes, moving from a diverse group of cells to the dominance of a better-adapted tumour clone. That gives clinicians and researchers a more precise target for future work while keeping the evidence within its limits.
