# Functional apoptosis profiling reveals vulnerabilities in T-cell large granular lymphocytic leukemia

## TL;DR

This study identifies MCL-1 as a potential therapeutic target in a subset of T-cell large granular lymphocytic leukemia patients through functional apoptosis profiling.

## Contribution

The study introduces functional apoptosis profiling to uncover targetable anti-apoptotic vulnerabilities in T-LGLL cells.

## Key findings

- CD8+ T-LGLL cells in 50% of patients showed a strong dependence on MCL-1.
- AZD-5991 induced apoptosis in T-LGLL cells with enhanced MCL-1 dependence.
- T-LGLL exhibits clinical, genetic, and functional heterogeneity.

## Abstract

T-cell large granular lymphocytic leukemia (T-LGLL) is a rare hematologic neoplasm characterized by clonal expansion of CD3 + cytotoxic T lymphocytes and a highly heterogeneous clinical course. Conventional therapy primarily includes immunosuppressive regimen. However, optimal front-line approaches still need to be defined and refractory disease remains a clinical challenge. Thus, we here aimed to explore functional dependencies of T-LGLL as a basis for personalized therapeutic strategies. We performed functional apoptosis profiling and ex vivo drug treatment in a series of 8 clinically and genetically characterized T-LGLL patients from two German University hospitals. Our series of patients underscored the clinical and genetic heterogeneity of the disease. Genetically, only 2 patients harbored a STAT3 mutation. To identify targetable anti-apoptotic mechanisms, we performed selective functional BH3 profiling on the patients’ CD8 + T-cells harboring the malignant T-LGLL cells versus the same patients’ normal CD4 + T-cells. CD8 + cells in 50% of the patients (4/8) demonstrated a dominant functional dependence on MCL-1 as compared to the same patients’ normal T-cells. Accordingly, CD8 + T-LGLL cells from patients with enhanced MCL1 dependence significantly responded to AZD-5991 ex vivo while no response was observed in the remaining samples lacking enhanced MCL-1 dependence. Across clinically and genetically heterogeneous cases of T-LGLL, functional apoptosis profiling identified patients with CD8 + T-LGLL cells harboring a dominant dependence on MCL-1 as a potential therapeutic target.

The online version contains supplementary material available at 10.1007/s00277-025-06230-3.

Our study highlights the clinical, genetic and functional heterogeneity of T-LGLL and provides an approach to decipher targetable anti-apoptotic mechanisms. In our series of T-LGLL patients, we provide insight in the heterogeneous functional dependence of T-LGLL cells on MCL-1 and effective induction of apoptosis using AZD-5991 in T-LGLL cells with enhanced MCL-1 dependence.

The online version contains supplementary material available at 10.1007/s00277-025-06230-3.