Subclonal STAT3 mutations solidify clonal dominance.

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Large granular lymphocyte leukemia (T-LGLL) is a clonal lymphoproliferative disorder linked to cytotoxic T-cell (CTL) responses.
• Absence of STAT3 mutations in some T-LGLL cases suggests antigen-driven expansion maintains clone persistence.

Purpose of the Study:

• To investigate the relationship between STAT3 mutations and CTL clonal selection in T-LGLL.
• To understand how STAT3 hits influence clonal dynamics during disease progression and in response to therapy.

Main Methods:

• Serial deep next-generation sequencing (NGS) of T-cell receptor (TCR) Vβ complementarity-determining region 3 (CDR3) and STAT3.
• Analysis of clonal hierarchy and dynamics in patients with T-LGLL.

Main Results:

• STAT3 mutations create subclones within monoclonal CTL populations, appearing early or during disease course.
• Therapy can eliminate or silence LGL clones, but clones may persist or be replaced by STAT3-negative CTLs.
• Persistent antigenic drive fuels LGL clone evolution, with STAT3 mutations accelerating the process or conferring autonomy.

Conclusions:

• STAT3 mutations play a significant role in the evolution and persistence of T-LGLL clones.
• Understanding these dynamics is crucial for predicting treatment response and managing T-LGLL.