Page 45 - Haematologica Vol. 110 - January 2025

PERSPECTIVE ARTICLE
T-cell clones of uncertain significance. When is the rogue clone dangerous?
Gianpietro Semenzato,1,2 Antonella Teramo,1,2 Giulia Calabretto1,2 and Renato Zambello1,2
1University of Padova, Department of Medicine, Hematology Unit and 2Veneto Institute of Molecular Medicine, Padova, Italy
Abstract
T-cell large granular lymphocyte clones that persist over time and that exhibit molecular and immunophenotypic features closely resembling those of T-cell large granular lymphocyte leukemia (T-LGLL) may be detectable in individuals who lack any clinical or laboratory features supporting a diagnosis of a T-cell malignancy. This condition represents a potential pre- cursor state termed T-cell clones of uncertain significance (T-CUS). T-CUS represents the even more benign extreme of the wide spectrum of clonal T-large granular lymphocyte proliferations, emphasizing the need for an appropriate multiparamet- ric diagnostic assessment that avoids misdiagnosis of T-cell neoplasia. This approach should overcome numerical cut-offs as the sole criteria to differentiate the benign condition from the related malignancies. In particular, genomic aberrancies might prospectively identify individuals who are at risk of progression to a full-blown T-cell malignancy. We herein discuss the significance of these T-cell clones in both healthy and disease states, suggesting molecular assays for tracking early steps of disease.
Introduction
T-cell clones of uncertain significance (T-CUS) exhibit mo- lecular and immunophenotypic features closely resembling those of T-cell large granular lymphocytic leukemia (T-LGLL). However, individuals harboring these rogue clones lack any clinical or laboratory features supporting a diagnosis of a T-cell malignancy.1-3
T-CUS is actually a premalignant condition detectable in otherwise healthy individuals and it is reminiscent of other precursor states involving the B-cell branch of immunity, such as monoclonal B-cell lymphocytosis (MBL) and mono- clonal gammopathy of undetermined significance (MGUS), as well as the myeloid compartment, e.g., clonal hemato- poiesis of indeterminate potential (CHIP).4 These conditions are identified by clones that manifest with an abnormal cell expansion and/or the increase of their by-products (monoclonal component).
T-CUS is being increasingly intercepted due to the avail- ability and use of new techniques that can uncover even small clones undetectable with conventional methods. As a result, more individuals are now being diagnosed with
this condition than in the past. Upon receiving this diag- nosis, patients understandably experience anxiety about a disorder defined as “clonal”. Furthermore, during follow-up visits, they are constantly reminded of the insidious nature of their abnormality, and addressing the prognosis and likelihood of progression to overt malignancy remains chal- lenging due to the limited knowledge on the matter. Only a few original papers have been published on T-CUS,2,3,5-8 well-documented prospective cohorts are not available, and currently there are no official clinical guidelines on the management of this condition.
Oligoclonal/clonal T-cell expansions might reflect the long- lived status of effector/memory cells specific to past in- fections.9-11 Otherwise, they might result from continuous antigenic stimulation by non-pathogenic infections as well as from any setting characterized by prolonged antigenic pressure, including allogeneic hematopoietic stem cell transplantation (HSCT), vaccinations and other stimuli.12 We herein discuss how to approach these T-cell clones and their significance in both healthy and disease states. These conditions need to be carefully considered and our understanding on the matter must be translated into an
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Correspondence: G. Semenzato g.semenzato@unipd.it
Received: Accepted: Early view:
June 10, 2024. September 25, 2024. October 3, 2024.
https://doi.org/10.3324/haematol.2024.286023
©2025 Ferrata Storti Foundation Published under a CC BY-NC license