Differential expression and function of A20 and TRAF1 in Hodgkin lymphoma and anaplastic large cell lymphoma and their induction by CD30 stimulation

Abstract

A20 and TRAF1 are two anti-apoptotic components of the intracellular signalling pathway of the tumour necrosis factor receptor (TNFR) family. Induction of apoptosis seems to be a main function of these receptors. It is astonishing that a member of this family, CD30, is overexpressed by highly proliferating tumours such as Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). It is known that CD30 stimulation leads to the apoptosis of ALCL tumour cells but not of Hodgkin-Reed-Sternberg (HRS) cells. We have already established the overexpression of TRAF1 in HRS cells. In this study we demonstrate that A20 is highly expressed in the HRS cells in 20/22 of cases of classical HL, in 4/4 cases of nodular lymphocyte-predominant HL (NLPHL), and in 2/2 cases of the anaplastic variant of diffuse large B cell lymphoma. In contrast, all other non-Hodgkin lymphomas, including ALCL, revealed either no A20 reactivity, or reactivity in less than 1% of all tumour cells. CD30 stimulation induced A20 and TRAF1 expression. This effect was most prominent in HL and ALCL cell lines with low basal expression levels of these molecules. Immunohistological studies of reactive lymphoid blasts in tonsillar tissue demonstrated that co-expression of CD30, A20, and TRAF1 also occurs in vivo. Cell lines with high basal A20 and TRAF1 expression were resistant to CD30-mediated apoptosis. The sensitivity to CD30-induced apoptosis was increased by inhibition of protein synthesis. TRAF1 transfection decreased CD30-induced apoptosis. Our data suggest that A20 and TRAF1 contribute to apoptosis resistance and, therefore, play an important role in the pathogenesis of classical HL.

Galectin-1-mediated cell death is increased by CD30-induced signaling in anaplastic large cell lymphoma cells but not in Hodgkin lymphoma cells

“…[21][22][23] TRAF1 is an anti-apoptotic molecule of the intracellular signaling pathway of TNFR family, the expression of which is induced by CD30 stimulation. 24 We confirmed that CD30 stimulation induced TRAF1 expression in Karpas 299, and in the present study we revealed that galectin-1 treatment did not influence this regulation (Figure 4). The CD30-mediated downregulation of TRAF2 is known to be a mechanism which negatively regulates CD30-induced NF-kB activation.…”

The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma

“…63 Of note, HRS cell lines with high basal expression of A20 and TRAF1 are reported to be resistant to apoptosis. 33 Taken together, these data suggest that in MLBCL, like cHL, signaling through TNF receptors and associated factors favors NF-B activation and resistance to apoptosis.…”

Cooperation between TNF Receptor-Associated Factors 1 and 2 in CD40 Signaling

“…Although other TRAFs are constitutively expressed in cells, TRAF1 expression is low in most resting cells but is up-regulated rapidly in response to NF-B and AP-1 activation by a diverse array of inflammatory mediators, including TNF-␣, CD40, LPS, and others (6 -12). TRAF1 expression is notably elevated in malignant lymphoid cells, including those of Hodgkin's disease, non-Hodgkin's lymphomas, and B cell chronic lymphocytic leukemia (11,66). However, the physiological significance of this enhanced TRAF1 expression is unclear.…”