Waldenström macroglobulinemia is a rare type of lymphoma that can evolve very differently from one patient to another. Now, a team of researchers from Clínic-IDIBAPS, within the framework of the Clínic Barcelona Comprehensive Cancer Centre, has led a study that provides new insights into the mechanisms driving this evolution and enabling specific populations of tumor cells to eventually dominate the disease.
The study, published in the journal HemaSphere, was coordinated by Carlos Fernández de Larrea, Head of the Hematology Department at Clínic and leader of the IDIBAPS research group Myeloma, Amyloidosis, Macroglobulinemia and Other Gammopathies; David F. Moreno, researcher in the same group; and Ferran Nadeu, researcher in the IDIBAPS Molecular Pathology of Lymphoid Neoplasms group.
The study combined state-of-the-art single-cell analysis technologies to characterize the origin, expansion, and heterogeneity of tumor cells in patients with IgM monoclonal gammopathy of undetermined significance (IgM MGUS), smoldering Waldenström macroglobulinemia, and symptomatic Waldenström macroglobulinemia.
A rare disease with highly variable evolution
Waldenström macroglobulinemia is a rare type of lymphoma that originates in B lymphocytes and is characterized by the production of a protein known as immunoglobulin M (IgM). The clinical course of the disease is highly heterogeneous: some individuals may remain symptom-free for years, whereas in other cases the disease progresses and requires treatment.
Before symptomatic disease develops, some patients experience a premalignant stage known as IgM monoclonal gammopathy of undetermined significance. Understanding how the transition between these stages occurs remains one of the main unanswered questions in this field of research.
Early stages show multiple B-cell clones
The analysis of more than 130,000 individual cells from bone marrow and blood samples revealed that the early stages of the disease are characterized by the coexistence of multiple B-cell clones. In contrast, a single tumor clone tends to predominate in more advanced forms of Waldenström macroglobulinemia.
According to the researchers, this finding suggests that the disease evolves from a more diverse initial scenario in which different cell populations compete with one another until one acquires biological advantages that allow it to expand and become dominant.
Mechanisms driving the expansion of the tumor clone
The study identified several molecular characteristics that distinguish dominant tumor cells from other B cells present in patients. Researchers found that these cells show particularly high activity of genes and regulatory mechanisms associated with cell growth and survival.
These findings provide new clues as to why certain cellular clones eventually outcompete others and become the main drivers of disease progression. “Among the potential players involved in this process, we identified several molecular markers that may help us better characterize tumor cells and understand how they expand,” explains David F. Moreno.
Genetic alterations associated with disease progression
Genetic analyses showed that certain chromosomal alterations are more frequent in patients with higher-risk forms of the disease. Among them, the loss of a segment of chromosome 6 stood out, an alteration that previous studies had already linked to a less favorable clinical outcome.
The researchers also confirmed the presence of characteristic mutations found in Waldenström macroglobulinemia, including mutations affecting the MYD88 gene, and observed that some of these alterations can appear at very early stages, before a tumor cell population becomes dominant.
“These results suggest that some of these genetic changes may provide growth advantages to specific cellular clones and thereby contribute to disease progression,” says Ferran Nadeu.
The influence of the immune microenvironment
The research shows that tumor cells do not evolve in isolation but instead maintain close interactions with other cells present in the bone marrow. In particular, the study detected especially intense communication between dominant tumor cells and monocytes, a type of white blood cell involved in immune responses.
This observation reinforces the idea that the microenvironment surrounding tumor cells may influence disease development and opens new avenues of research to better understand these mechanisms.
A new perspective on disease origin and evolution
“By integrating genomic, transcriptomic and epigenetic information at the single-cell level, we were able to reconstruct with great precision how Waldenström macroglobulinemia evolves,” says Carlos Fernández de Larrea. “Our findings indicate that the disease emerges from an initial setting in which different B-cell clones coexist, but one of them gradually acquires biological advantages that allow it to expand and outgrow the others.”
The study contributes to a better understanding of the mechanisms driving the progression of Waldenström macroglobulinemia and identifies new elements that could help improve patient stratification and guide future therapeutic strategies, although these findings will need to be validated in larger studies.
Study reference:
Moreno DF, Nadeu F, Casado-Peláez M, Mata C, Márquez-López I, Fernández MA, Vaqué S, Medina E, Llobregat H, Garrote M, Mañé J, Cardús O, Rodríguez-Lobato LG, de Daniel A, Cibeira MT, Gremen Oliveira T, Kulaeva E, Lozano E, Colomer D, Rosiñol L, van Boxtel R, Esteller M, Fernández de Larrea C. Clonotypic characterization defines B-cell drivers of clonal expansion and intratumor heterogeneity in IgM monoclonal gammopathies. Hemasphere. 2026 Sep 12;10(9):e70456. doi: 10.1002/hem3.70456.
