Monoclonal B-cell lymphocytosis, monoclonal gammopathy of undetermined significance, and T-cell clones of uncertain significance: are these premalignant conditions sharing a common identity?

Monoclonal B-cell lymphocytosis, monoclonal gammopathy of undetermined significance, and T-cell clones of uncertain significance are three premalignant conditions characterised by the presence of small clonal cell expansions in individuals without symptoms or signs that distinguish the related overt malignancies (chronic lymphocytic leukaemia, multiple myeloma, and T-cell large granular lymphocytic leukaemia). As most individuals with these precursor states never progress to malignancies, considerable interest has arisen in comprehending the steps involved in the progression to malignancy, providing more accurate models to investigate potential mechanisms of early blood cancer identification, prevention, and, possibly, intervention. Single-cell technologies and recent progress in high-throughput sequencing and multiomics approaches have contributed to a better definition of the pathophysiological mechanisms of these premalignant conditions, moving our knowledge in the field forward. In this Viewpoint, we analyse the seemingly shared biological trajectories in these precursor haematological malignancies in search of common pathogenetic events. In particular, we address the issue of interactions between expanding clones and their immune ecosystem, offering new clues that might prompt innovative ideas and inspire further investigations to understand the cellular and molecular dynamics entailing progression into overt malignant disease. The relationships between the non-leukaemic microenvironmental cells and the leukaemic counterpart, and the primary drivers of their initial clonal expansion, represent shared biologies that suggest a common identity among the premalignant conditions considered in this Viewpoint.