CD30 Expression and Its Functions during the Disease Progression of Adult T-Cell Leukemia/Lymphoma

Abstract

CD30, a member of the tumor necrosis factor receptor superfamily, plays roles in pro-survival signal induction and cell proliferation in peripheral T-cell lymphoma (PTCL) and adult T-cell leukemia/lymphoma (ATL). Previous studies have identified the functional roles of CD30 in CD30-expressing malignant lymphomas, not only PTCL and ATL, but also Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), and a portion of diffuse large B-cell lymphoma (DLBCL). CD30 expression is often observed in virus-infected cells such as human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 is capable of immortalizing lymphocytes and producing malignancy. Some ATL cases caused by HTLV-1 infection overexpress CD30. However, the molecular mechanism-based relationship between CD30 expression and HTLV-1 infection or ATL progression is unclear. Recent findings have revealed super-enhancer-mediated overexpression at the CD30 locus, CD30 signaling via trogocytosis, and CD30 signaling-induced lymphomagenesis in vivo. Successful anti-CD30 antibody-drug conjugate (ADC) therapy for HL, ALCL, and PTCL supports the biological significance of CD30 in these lymphomas. In this review, we discuss the roles of CD30 overexpression and its functions during ATL progression.

Keywords: ATL; CD30 (TNFRSF8); CD30L (TNFSF8); HTLV-1; TNFRSF; TNFSF; lymphomagenesis; super-enhancer; trogocytosis.

Figure 1

CD30 signaling via trogocytosis. (A) CD30 binds to trimerized CD30L, and, subsequently, recruits TRAF1, 2, 3, and 5 to the intracellular domain of CD30 molecules. Activation of TRAFs triggers downstream signal transduction and induces nuclear translocation of RelA-p50 and C-rel-p50, and RelB-p52, known as the canonical and non-canonical pathways, respectively. This signal transduction elicits various cellular signaling responses, including proliferation, survival, cytokine secretion, and cell death, depending on the cell type and the cellular differentiation state. (B) On the contact surface of CD30L and CD30-expressing cells, CD30L and CD30 form huge clusters, with CD30 extracting CD30L from the adjoining cell, along with part of their plasma membrane, triggering internalization of the clustered complex. These complexes simultaneously generate signalosomes, resulting in intracellular signaling, and are, subsequently, degraded in lysosomes. This phenomenon represents trogocytosis-mediated signal transduction.

Figure 2

The mechanisms of CD30 gene induction. (A) The CpG island encompassing 60 CpG dinucleotides is located in the promoter region, exon 1, and intron 1 of the CD30 gene locus. The CpG island maintains a hyper-methylated state in non-lymphoid lineage cells and a hypo-methylated state in lymphoid lineage cells ((i) and (ii), respectively). These results suggest that the 60 CpG state on the CD30 promoter, exon 1, and a part of intron 1 controls the transcriptional induction of the CD30 gene. (B) JunB binds at −377 to −371 bp from the TSS in the microsatellite sequences in HL and ALCL. IRF4, STAT3, and BATF3 bind to the CD30 promoter region in ALCL. These transcriptional factors induce transcriptional activity. Furthermore, the super-enhancer is formed on the CD30 gene locus in ALCL and ATL cell lines and these patient-derived tumor cells.

Figure 3

CD30 signal-induced chromosomal instability in ATL cells. CD30 signaling triggers chromosomal instability with clonal expansion in the ATL cell line and primary CD30⁺ ATL cells. CD30 signaling induces an increase in intracellular ROS without inducing apoptosis and promotes DSBs in a CD30 expression level-dependent manner. These results suggest that CD30 signaling is one of the oncogenic factors of ATL progression with clonal evolution.