Clonal drift demonstrates unexpected dynamics of the T-cell repertoire in T-large granular lymphocyte leukemia

Abstract

T-cell large granular lymphocyte leukemia (T-LGLL) is characterized by chronic

Detection of monoclonal T populations in patients with KIR-restricted chronic lymphoproliferative disorder of NK cells

“…By flow cytometry, in nearly 50% of the patients with T-LGLL studied, Clemente et al reported the phenomenon recognized as clonal drift in the Vb usage. 18 These authors observed that the clone size was smaller in the clonal drift group with respect to stable patients, supporting the concept that we are dealing with an early manifestation of the disease. CDR3 AA sequence was also shown to remain unaltered in stable clones, whereas expansions with different Vb restriction presented markedly different CDR3 sequences, suggesting that clonal drift was not associated with a conserved TCRg homology.…”

“…a change in the dominant T-cell clone observed in nearly 50% of LGLL patients, has been interpreted in line with this hypothesis. 18 Similarly, in both disorders, in vivo activation of STAT3 and the presence of somatic STAT3 mutations have been observed. [19][20][21][22] The observation that STAT3 SH2 somatic mutations can be found with a similar frequency in NK-cell and in T-cell disorders further indicates that a common mechanism is responsible for their pathogenesis, possibly driven by a shared genetic lesion irrespective of the cell lineage.…”

The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia

“…The presence of several STAT3 mutations could also be related to the clonal drift phenomenon, where the immunodominant LGL clone changes. 28 In addition, STAT3-mutated clones may carry somatic mutations in other genes, which affect the proliferative capacity of affected lymphocytes. These mutations could also drive the lymphoproliferation in patients without STAT3 mutations.…”

“…It was established earlier that the major clones in CD8 + T-LGL leukemia patients are rarely identical, but the immunodominant clones are sometimes seen at a low frequency in other patients when the whole TCRB repertoire is analyzed. 28,[34][35][36] It should, however, be noted that the specific antigen can be recognized by a large number of different TCR types depending on the peptide presented, and the variation of HLA genes also affects antigen recognition. 37,38 The presence of a shared antigen driving the LGL proliferation has not, therefore, been ruled out, although our current understanding suggests more private antigens.…”

Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia

“…Taking together, these results indicate that genomic mutations might only marginally account for in vivo activation of STAT3 in patients with LGLL and further emphasize the heterogeneity of mechanisms sustaining LGLL, highlighting the plasticity of proliferating cells. 43 …”