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Review
. 2022 Mar 10:12:849917.
doi: 10.3389/fonc.2022.849917. eCollection 2022.

Cytokines in the Pathogenesis of Large Granular Lymphocytic Leukemia

Colleen Isabelle  1 , Amy Boles  1 , Nitin Chakravarti  1 , Pierluigi Porcu  1 , Jonathan Brammer  2 , Anjali Mishra  1   3
Affiliations
Review

Cytokines in the Pathogenesis of Large Granular Lymphocytic Leukemia

Colleen Isabelle et al. Front Oncol. .

Abstract

Large granular lymphocytic leukemia (LGLL) is a lymphoproliferative disorder of older adults characterized by the clonal expansion of cytotoxic T/natural killer cells due to constitutive pro-survival signaling. In recent years, it has become clear that cytokines and their receptors are aberrantly expressed in LGLL cells. The exact initiation process of LGLL is unknown, although several cytokine-driven mechanisms have emerged. Elevated levels of several cytokines, including interleukin-15 (IL-15) and platelet-derived growth factor (PDGF), have been described in LGLL patients. Evidence from humans and animal models has shown that cytokines may also contribute to the co-occurrence of a wide range of autoimmune diseases seen in patients with LGLL. The goal of this review is to provide a comprehensive analysis of the link between cytokines and pro-survival signaling in LGLL and to discuss the various strategies and research approaches that are being utilized to study this link. This review will also highlight the importance of cytokine-targeted therapeutics in the treatment of LGLL.

Keywords: LGLL; cytokines; growth factors; interleukins; therapy.

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Conflict of interest statement

JB, AM, and PP have received funding from pharmaceutical companies for research and clinical trials. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Contribution of critical cytokine signaling to large granular lymphocytic leukemia (LGLL) immunopathogenesis. Interleukin (IL)-15, platelet-derived growth factor (PDGF), IL-2, and IL-6 are all central players in the immunopathogenesis of LGLL. Dysregulation of these cytokines leads to constitutive activation of their downstream signaling pathways such as PI3K, JAK/STAT, Ras/MAPK, and NF-kB. This leads to increased transcription of oncogenic driver genes such as c-MYC, cyclin D1, and BCL-xL, ultimately leading to increased malignant cell proliferation and survival. Figure made with BioRender.com.
Figure 2
Figure 2
Cytokine-directed therapies of interest in large granular lymphocytic leukemia (LGLL). Mik-β1, a CD122 monoclonal antibody, prevents the trans-presentation of interleukin (IL)-15. BNZ-1 binds the common gamma chain CD132, blocking IL-15 and IL-2 signaling. Siltuximab and tocilizumab block IL-6 signaling. Imatinib mesylate is a receptor tyrosine kinase inhibitor that prevents platelet-derived growth factor (PDGF) signaling. Secukinumab and ixekizumab block IL-17 signaling. Risankizumab binds the p19 subunit of IL-23 to block signaling. Figure made with BioRender.com.
See this image and copyright information in PMC

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