Universität zu Köln

Klepzig, Hanna ORCID: 0009-0007-8369-8115, Herling, Marco, Pflug, Natali ORCID: 0000-0002-3895-7065 and Braun, Till ORCID: 0000-0002-0854-7815 (2025). Models for T-large granular lymphocytic leukemia: how to mimic the cellular interplays in malignant autoimmunity. Leukemia, 39 (4). pp. 792-804. Springer Nature. ISSN 0887-6924

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Abstract

T-large granular lymphocytic leukemia (T-LGLL) is a chronic lymphoproliferative disorder characterized by clonal expansions of cytotoxic T-cells. It presents with cytopenias that are not explained by the typically low leukemic burden. Notably, T-LGLL is frequently accompanied by autoimmune disorders, particularly rheumatoid arthritis (RA). As clonal T-cell expansions are also increasingly identified in autoimmune-driven conditions, better models of T-LGLL’s pathogenesis as a spectrum of (auto)antigen-driven oligoclonal hierarchies towards overt leukemic escape with associated immune dysregulations would provide details to a valuable prototype for determinants of T-cell fitness and transformation as well as T-cell instructed dysfunctions of other immune cells. Such insights would advance our concepts of cancer biology and immunology. Common molecular links between T-LGLL and autoimmune diseases include activation of JAK/STAT signaling, proinflammatory cytokine environments, and antigen-driven immune responses. Current murine models address these mechanisms rather individually: JAK/STAT based systems replicate pathway activation, cytokine-driven models simulate inflammatory conditions, and RA models often mimic antigen stimulation. However, none of these fully captures the duality of clonal T-cell expansion and the complex immune dysregulations, inherent to T-LGLL. This review examines criteria for autochthonous in-vivo T-LGLL models and evaluates existing systems, identifying their strengths, limitations, and specific representations of clinico-pathologic aspects of LGLL. Prominent transgenic models, for example, not only manipulate the T-cell compartment but also indiscriminately alter the tumor microenvironment, impeding research on the specific role of elements of the LGLL micromilieu. We propose strategies to overcome such insufficiencies of present models. Overall, our critical appraisal emphasizes the need for novel comprehensive models that more faithfully integrate the key features of T-LGLL or for models that, by featuring specific pathogenetic aspects of the disease, would supplement existing incomplete systems. We expect such new model systems to aid in better understanding the cancer-immunity interface and in assessing novel therapeutic approaches for T-LGLL.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Klepzig, Hanna UNSPECIFIED https://orcid.org/0009-0007-8369-8115 UNSPECIFIED Herling, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Pflug, Natali UNSPECIFIED https://orcid.org/0000-0002-3895-7065 UNSPECIFIED Braun, Till UNSPECIFIED https://orcid.org/0000-0002-0854-7815 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-797181
Identification Number:	10.1038/s41375-025-02553-2
Journal or Publication Title:	Leukemia
Volume:	39
Number:	4
Page Range:	pp. 792-804
Number of Pages:	13
Date:	7 April 2025
Publisher:	Springer Nature
ISSN:	0887-6924
Language:	English
Faculty:	Central Institutions / Interdisciplinary Research Centers Faculty of Medicine
Divisions:	Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie Faculty of Medicine > Sonstiges > Centrum für integrierte Onkologie (CIO)
Subjects:	Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79718