New JAK3-INSL3 Fusion Transcript—An Oncogenic Event in Cutaneous T-Cell Lymphoma

Abstract

Constitutively activated tyrosine kinase JAK3 is implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCL). The mechanisms of constitutive JAK3 activation are unknown although a JAK3 mutation was reported in a small portion of CTCL patients. In this study, we assessed the oncogenic roles of a newly identified JAK3-INSL3 fusion transcript in CTCL. Total RNA from malignant T-cells in 33 patients with Sézary syndrome (SS), a leukemic form of CTCL, was examined for the new JAK3-INSL3 fusion transcript by RT-PCR followed by Sanger sequencing. The expression levels were assessed by qPCR and correlated with patient survivals. Knockdown and/or knockout assays were conducted in two CTCL cell lines (MJ cells and HH cells) by RNA interference and/or CRISPR/Cas9 gene editing. SS patients expressed heterogeneous levels of a new JAK3-INSL3 fusion transcript. Patients with high-level expression of JAK3-INSL3 showed poorer 5-year survival (n = 19, 42.1%) than patients with low-level expression (n = 14, 78.6%). CTCL cells transduced with specific shRNAs or sgRNAs had decreased new JAK3-INSL3 fusion transcript expression, reduced cell proliferation, and decreased colony formation. In NSG xenograft mice, smaller tumor sizes were observed in MJ cells transduced with specific shRNAs than cells transduced with controls. Our results suggest that the newly identified JAK3-INSL3 fusion transcript confers an oncogenic event in CTCL.

“Next top” mouse models advancing CTCL research

“…These studies underscore the importance of CTCL heterogeneity and highlight the therapeutic potential of coordinated treatments ( Netchiporouk et al, 2017 ; Gallardo et al, 2018 ; Zhang et al, 2018 ; Froehlich et al, 2019 ; Wang et al, 2020 ; Poglio et al, 2021 ; Wu et al, 2021 ). Recent advancements include the superior performance of CCR4-IL2 immunotoxin ( Wang et al, 2023 ), RT39 peptide therapy ( Habault et al, 2022 ), novel drug NT1721 ( Lin et al, 2021 ), JAK3-INSL3 fusion transcripts ( Velatooru et al, 2023 ), anti-CCR4 CAR T cells ( Watanabe et al, 2023 ), universal CD2 CAR-T therapy ( Xiang et al, 2023 ) and the antibody-drug conjugate SGN-CD70A ( Wu et al, 2022 ) have further expanded the therapeutic research landscape for CTCL.…”

Janus Kinase 3 (JAK3): A Critical Conserved Node in Immunity Disrupted in Immune Cell Cancer and Immunodeficiency

“…A large number of mutations in JAK3 have been identified in immune cell cancers, the majority being within the pseudo-PTK and PTK domains, with the most common being M511I, A573V and R657A in the pseudo-PTK domain, although no clear correlation of specific mutations with cancer type has been identified [ 39 ] ( Figure 3 ). A JAK3–INSL3 fusion transcript has also been reported in CTCL [ 40 ]. JAK3 GOF mutations have been collectively found to result in constitutive tyrosine-phosphorylation and the ability to elicit factor-independent growth of relevant cell lines [ 26 , 32 , 41 ].…”