Mutational Spectrum of T-Cell Large Granular Lymphocytic Leukemia - Insights From the AACR Project GENIE Consortium - abstract

Sep 28, 2026

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Rare, indolent T-cell large granular lymphocyte leukemia (T-LGLL) is examined through genomic profiling to characterize somatic alterations and refine the molecular landscape using population-focused biomarkers. A retrospective analysis of T-LGLL samples is performed using the AACR Project GENIE database, extracting patient demographics and excluding synonymous mutations. Somatic mutations and copy number variations are assessed with chi-squared testing and RStudio-based computational analyses, defining significance at p=0.001. Recurrent mutations and dysregulated signaling, especially FAS-FASL, are identified as potential therapeutic targets.

LanguageEnglish

CategoryHealthcare

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Abstract

Background/Aim

Materials and Methods

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Introduction

Overview and classification

Risk factors and epidemiology

Diagnosis and treatment

doi: 10.21873/cgp.20566 Mutational Spectrum ofT-Cell Large Granular Lymphocytic Leukemia: Insights From theAACR Project GENIE Consortium BHANU SURABI UPADHYAYULA1, GRACES. SAGLIMBENI2, EDIEGOBEL3, ABBIGOBEL3, TYSON J. MORRIS2, AKAASH SURENDRA3, BEAU HSIA2, AKSHATSOOD4 and ABUBAKARTAUSEEF4 1School of Biological Sciences, University of California, Davis, CA, U.S.A.; 2School of Medicine, Creighton University, Phoenix, AZ, U.S.A.; 3School of Life Sciences, Arizona State University, Tempe, AZ, U.S.A.; 4School of Medicine, Creighton University, Omaha, NE, U.S.A. Abstract Background/Aim: T-cell large granular lymphocyte leukemia (T-LGLL) is a rare, indolent lymphoproliferative disorder of cytotoxic T cells in the peripheral blood, bone marrow, and spleen. This analysis was conducted to characterize genomic alterations and highlight potential therapeutic targets, with the goal of refining the molecular landscape of T-LGLL by emphasizing population-specific biomarkers. Materials and Methods: This study utilized the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database to identify common gene mutations. Using the AACR GENIE database, a retrospective analysis of T-cell large granular lymphocyte leukemia (T-LGLL) samples was performed. The data was evaluated by extracting patient demographics and excluding synonymous mutations from consideration. Statistical significance was assessed using chi-squared tests and computational analyses in RStudio (R Foundation for Statistical Computing, Boston, MA, USA). Somatic mutations and chromosomal copy number variations were evaluated, with statistical significance defined as p=0.001 . Results: Frequently observed somatic mutations included STAT3 (41.7%), STAT2 (20.9%), KMT2D (11.3%), SETD1B (8.7%), TP53 (7.0%), TNFAIP3 (6.1%), DNMT3A (5.2%), FAS (4.3%), SMARCA4 (3.5%), EPHB1 (2.6%), KSR2 (2.6%), ALOX12B (2.6%), EGFR (2.6%), DDX3X (7.0%), and IKZF3 (1.7%). When stratified by demographic variables, males and White patients demonstrated a higher frequency of mutations. Conclusion: This study provides a comprehensive genomic profile ofT-LGLL, identifying recurrent somatic mutations and commonly affected pathways. Notably, frequent alterations were observed in the FAS-FASL signaling pathway, underscoring its potential as a target for therapeutic development. Keywords: T-cell large granular lymphocyte leukemia (T-LGLL), American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE), STAT2, KMT2S, FAS, somatic mutations. ✉Abubakar Tauseef, School of Medicine, Creighton University, Omaha, NE, U.S.A. E-mail: [abubakartauseef@creighton.edu](abubakartauseef@creighton.edu) Received September 8, 2025 | Revised September 29, 2025 | Accepted October 21, 2025 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. ©2026 The Author(s) . Anticancer Research is published by the International Institute of Anticancer Research. Introduction T-cell large granular lymphocyte leukemia (T-LGLL) is a rare, indolent lymphoproliferative disorder characterized by the proliferation of cytotoxic T cells, affecting the peripheral blood, bone marrow, and spleen. In the fifth edition of the World Health Organization (WHO) classification, T-LGLL is categorized under “Mature T-cell and NK-cell leukemias”(1) . Peripheral blood smears typically reveal intermediate-sized lymphocytes with round to slightly irregular nuclei, reticulated chromatin, and abundant pale cytoplasm containing azurophilic granules (2). Most patients areasymptomatic at diagnosis and are later identified after developing recurrent or severe infection (2) . T-LGLL carries a mean overall survival of approximately 10 years, with the majority of deaths attributed to severe

FAQs

What is the main purpose of the AACR GENIE analysis in this study?

To characterize genomic alterations in T-LGLL and highlight potential therapeutic targets by refining the molecular landscape with population-specific biomarkers.

Which database and statistical approach are used to identify mutations?

The AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) database is used for retrospective mutation identification, with chi-squared tests and RStudio-based computational analyses; significance is set at p=0.001.

What recurrent mutations and pathway are emphasized in the results?

Frequently observed somatic mutations include STAT3, STAT2, KMT2D, SETD1B, and TP53, and frequent alterations are noted in the FAS-FASL signaling pathway, suggesting it as a therapeutic target.

Sep 28, 2026

Uploaded by dhado