Loss of Fas (CD95/APO-1) Regulatory Function Is an Important Step in Early MALT-Type Lymphoma Development

Abstract

SUMMARY:Fas (CD95, APO-1) mutations were found in autoimmune diseases and some lymphomas, suggesting impairment of Fas-mediated cell death signaling that may cause tumor development. Because mucosa-associated lymphoid tissue (MALT)-type lymphoma B cells recognize autoantigens and proliferate in response to antigen and T cell-mediated signals, it is suggestive that autoreactive B cell lymphoma precursor cells may have escaped the Fas-mediated checkpoint that normally operates in healthy individuals. Using different biochemical, molecular, and functional approaches, we analyzed the Fas signaling in malignant B cells from seven MALT-type lymphomas that were additionally characterized for the t(11;18)(q21;q21) and four gastric diffuse large B cell lymphomas (DLBL). All DLBLs and three of seven MALT-type lymphomas were resistant to Fas-mediated apoptosis in vitro. Moreover, four of five MALT-type lymphomas analyzed and one of three DLBLs analyzed showed mutations in Fas mRNA transcripts but no loss of heterozygosity in the Fas promotor region. Alternative mechanisms of resistance to apoptosis, such as decreased expression of Fas or production of soluble Fas were not operative. Therefore, it is suggestive that a subgroup of MALT-type lymphoma B cells, irrespective of t(11;18)(q21;q21), escape the censoring Fas pathway by mutating and inactivating Fas. This identifies a key regulatory step in early MALT-type lymphomagenesis. (Lab Invest 2001, 81:977-986).M arginal zone B cell lymphomas of mucosaassociated lymphoid tissue (MALT)-type are neoplastic counterparts of normal memory B cells (Harris et al, 1994). The development from naive to memory B cells is closely accompanied and regulated by T cells through Fas/FasL interaction (Nagata, 1997;Suda et al, 1993) taking place in the germinal centers of follicles and leading either to deletion of autoantigen-recognizing B cells or to further differentiation into memory B cells resident in the marginal zone of the follicle (Goodnow, 1996;Rathmell et al, 1996) and plasma cells. Therefore, disruption of the Fas/FasL apoptotic pathway is associated with lymphoproliferative and autoimmune disorders as demonstrated in mice carrying lymphoproliferation (lpr) or generalized lymphoproliferative disease (gld) mutations affecting the genes for Fas and FasL, respectively (Takahashi et al, 1994;Watanabe-Fukunaga et al, 1992), or in humans carrying inherited mutations in the Fas gene leading to autoimmune lymphoproliferative syndrome (Bettinardi et al, 1997;Fisher et al, 1995;Rieux Laucat et al, 1995;Sneller et al, 1997). Because autoantigen receptors and marginal zone B cell expansions are characteristic features of MALT-type lymphoma , we searched for a link between tumor development and functionality of the Fas/FasL apoptotic pathway. In addition, the translocation t(11;18)(q21;q21) is the most characteristic chromosomal aberration in extranodal MALT-type lymphoma and may interfere with the regulation of apoptosis. In recent studies, the gene for the human inhibitor of apoptosis protein...

Tumor suppressor genes in normal and malignant hematopoiesis

“…Disruption of the TGFb signalling pathway by mutations of the SMA-and MAD-related protein 4 (SMAD4) can be found in AML (Imai et al, 2001). Apoptotic pathways may be disrupted by mutations of CD95 (Fas/APO-1) in NHL (Xerri et al, 1995;Gronbaek et al, 1998;Straus et al, 2001;Seeberger et al, 2001), T-ALL (Beltinger et al, 1998) and multiple myeloma (Landowski et al, 1997) or by mutations of B-cell leukemia 2 associated X protein (BAX) in various leukemia and lymphoma cell lines (Meijerink et al, 1998;Inoue et al, 2000). Also, genes of the checkpoint of the G2 to M transition of the cell cycle might play a role in malignant transformation, as mutations of mitotic checkpoint genes budding uninhibited by benzimidazoles 1 (BUB1) and BUB related 1 (BUBR1) in ATL and B-NHL (Ohshima et al, 2000) and of mitotic arrested-de®cient 1 yeast homologue-like 1 (MAD1L1) in a single case of B-NHL ) might suggest.…”

Ocular adnexal lymphoma: a review of clinicopathologic features and treatment options

“…70 This hypothesis is based on the absence of T-cytotoxic lymphocyte regulation on H pylori-induced B-cell proliferation. 71 This last observation emphasizes the role of bacterial infection in this particular subtype of lymphoma.…”

Frequent mutations of Fas gene in nasal NK/T cell lymphoma

“…Mutations of Fas gene were detected in seven of 14 (50%) present cases of nasal NKTCL. Relatively high frequency of Fas gene mutations was reported in cases with thyroid lymphoma (65.4%) (Takakuwa et al, 2001) and other kinds of malignant lymphoma of mucosa-associated lymphoid tissue (MALT) type (Seeberger et al, 2001), although this remains a subject of controversy (Bertoni et al, 2000). It is well-recognized that follicular gastritis caused by the infection of Helicobacter pylori Figure 1 Summary of the Fas gene mutations found in patients with nasal NKTCL.…”