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• W3112508082 abstract "T-cell-specific surface glycoprotein CD28 belongs to the subfamily of costimulatory molecules characterized by an extracellular immunoglobulin variable-like domain. Other members of the subfamily include inducible T-cell costimulator (ICOS), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), programmed cell death-1 (PD1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and others. Naïve T cells are activated by two signals. The first involves antigen-specific T-cell receptor (TCR) signalling, and the second is antigen-non-specific and requires signalling through costimulatory receptors, of which the best characterized is the interaction of CD28 on T cells with CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells. CD28 is expressed constitutively on both resting and activated T cells, whereas the expression of other members of the family, ICOS and CTLA4, is induced by TCR stimulation.1 CTLA4 has a higher affinity for CD80 and CD86 receptors than CD28, and when CTLA4 is expressed on T cells predominantly, CD80 and CD86 are occupied by CTLA4, and CD28 cannot bind to CD80 and CD86 and T-cell activation is suppressed. The cytoplasmic region of CD28 contains two main signalling motifs, the membrane-proximal YMNM motif and two proline-rich motifs. When CD28 binds to its ligands, protein tyrosine kinases are recruited to the CD28 cytoplasmic tail and they phosphorylate CD28, which in turn recruits several adaptor proteins, including the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K), growth factor receptor-bound protein 2 (GRB2), and GRB2-related adaptor protein 2 (GADS), to its YMNM motif, and these interactions activate mitogen-activated protein kinase (MAPK), nuclear factor of activated T cells (NFAT), nuclear factor-κB (NF-κB) and AKT, leading to T-cell activation, cytokine production and proliferation.2 Genetic alterations of the CD28 gene have been reported in haematologic malignancies including angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) or cutaneous T-cell lymphoma (CTCL).3-5 Using genome-wide sequencing, Kataoka et al.6 reported that the most common genetic alterations in adult T-cell leukaemia/lymphoma (ATL), which is a mature T-cell neoplasm associated with the human T-cell leukaemia virus type 1 (HTLV-1), involves the TCR–NF-κB signalling pathway. In RNA-seq analysis of 57 ATL samples, five CD28 fusions (CTLA4–CD28 and ICOS–CD28) were detected, where the 5' part of the CTLA4 or ICOS genes was fused to the 3′ part of the CD28 gene.6 These fusions arrange for the cytoplasmic portion of CD28 to be expressed under the control of the regulatory elements of CTLA4 or ICOS and may lead to constitutive CD28 signalling activation.7 Gain of function mutations (F51I/V and D124E/V) in the CD28 genes8 were also described in eight cases out of 370 cases (2%).6 The substitutions were located in the highly conserved B7 ligand-binding sites and the bases were replaced by amino acids specific to CTLA4 or ICOS. Furthermore, recurrent focal copy number gain was detected in the CD28 locus (75 of 426 cases, 18%).6 In their paper the authors investigated the association between CD28 gene alterations and clinical outcome in a cohort of ATL patients. As expected, they found gene fusions, activating mutations, and gene amplification in the CD28 genes. Among the 144 ATLL patients, gene fusions between ICOS exon 1 and CD28 exon 2 and between CTLA4 exon 3 and CD28 exon 4 were detected in 14 patients (10%) by multiplex reverse transcription polymerase chain reaction (RT-PCR) analysis. Moreover, two types of CD28-activating mutations, F51I/V and D124E/V were detected in three patients (2%) by utilizing the SNaPshot method,9 and CD28 copy number gain or amplification was detected in 34 patients (24%) by fluorescence in situ hybridization (FISH) analysis. Notably, patients with CD28 gene alterations were revealed to be younger than those without (60 vs. 66 years).10 Allogeneic haematopoietic stem cell transplantation (HSCT) is the only available curative treatment for patients with aggressive ATL; however, transplant-related mortality is high. Therefore, the authors studied the association of CD28 gene alterations with overall survival (OS) in ATL patients with and without allogeneic HSCT treatment. In patients receiving allogeneic HSCT, five-year OS rates were not significantly different between those with and those without CD28 gene alterations. On the other hand, five-year OS of patients with or without CD28 gene alterations (n = 30 and n = 79 respectively) was 32·8% and 48·4%, respectively, and CD28 gene alterations showed significant interactions with patient survival. Specifically, CD28 mutations or CD28 amplification conferred a worse effect on prognosis in this cohort (Sakamoto et al., 2020). Another important finding reported by Sakamoto et al.10 is that patients with chronic or smouldering ATL subtypes, the indolent forms that are usually managed with watchful waiting until disease progression, have worse survival outcomes if they harbour CD28 gene alterations. Yoshida et al.11 recently reported that CTLA4–CD28 and ICOS–CD28 fusions were frequently (37·5%) detected especially in younger ATL patients under the age of 50 years, and mutations of PLCG1 and PRKCB, which were the most common driver mutations in ATL,6 were not identified in these subjects. Taken together, these observations support the notion that CD28 gene alterations may be associated with clonal proliferation of ATL cells, likely through continuous, prolonged and enhanced CD28 signalling. TCR/CD28 costimulation induces NF-κB activation in T cells and the constitutive activation of NF-κB has been reported to elicit epigenetic reprogramming of HTLV-1-infected T cells or ATL cells.12 Therefore, the enhanced CD28 signalling may predispose cells to malignant transformation and/or clonal proliferation. It should be noted that NF-κB is activated by multiple mechanisms in both HTLV-1 Tax-dependent and -independent manner.13 Therefore, identifying new downstream genes and processes regulated by CD28 would be important for the development of novel molecular targeted therapy for ATL. In conclusion, Sakamoto et al.10 highlight the importance of CD28 gene alterations as clinically relevant genetic changes in ATL. These findings also underscore a novel role for these abnormalities in the early stages of leukaemogenesis and during the development of ATL. Thus, CD28 signalling is a worthy target for future therapeutic studies in ATL." @default.
• W3112508082 created "2020-12-21" @default.
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• W3112508082 date "2020-12-14" @default.
• W3112508082 modified "2023-10-17" @default.
• W3112508082 title "The role of CD28 in adult T‐cell leukaemia/lymphoma" @default.
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• W3112508082 doi "https://doi.org/10.1111/bjh.17214" @default.
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