Serological identification of adult T‐cell leukaemia‐associated antigens

Abstract

SummaryAdult T-cell leukaemia (ATL) is a peripheral T-cell neoplasm caused by human T-cell leukaemia virus type I (HTLV-I). Several clinical observations suggest that some tumour-associated antigens in ATL may be recognised by the immune system. In this study, we performed the serological screening of an expression library to identify ATL-associated antigens by using materials from a unique ATL patient with long-term stable disease. Among five distinct genes isolated, serine/arginine protein kinase 1 (SRPK1), which has been reported to have a restricted normal tissue distribution, was found to be overexpressed in most acute type ATL samples, but not in chronic type ATL or in normal peripheral blood mononuclear cells by real-time reverse transcription polymerase chain reaction. Interestingly, the overexpression of SRPK1 in aggressive types of ATL was more exclusively observed at the protein level than at the mRNA level. Autologous antibody to SRPK1 was confirmed in the ATL patient using Western blot analysis with plasma, but not detected in asymptomatic HTLV-I carriers or in healthy volunteers. These results indicate that SRPK1 may be useful for the development of therapeutic and diagnostic methods for patients with ATL.

Targeting the RNA Splicing Machinery as a Novel Treatment Strategy for Pancreatic Carcinoma

“…In contrast, the ubiquitous expression pattern of SRPK1, its ability to activate a diverse array of SR protein splice factors, and our demonstration that it is increased in tumors of different origin provide a persuasive hypothesis that it serves a more global role in the missplicing observed across tumor systems. This premise is supported by a recent report by Hishizawa et al (35), showing the overexpression of SRPK1 in acute type adult T-cell leukemia (ATL) but not in chronic ATL or normal peripheral blood mononuclear cells, as well as the presence of autologous antibody to SRPK1 in the acute ATL patients. Figure 5.…”

The Akt-SRPK-SR Axis Constitutes a Major Pathway in Transducing EGF Signaling to Regulate Alternative Splicing in the Nucleus

“…Our current findings add a dimension in understanding diverse disease phenotypes from the prospective of regulated splicing, because dysregulation of RNA splicing has been attributed to many different kinds of human diseases (Cooper et al, 2009). Potential roles of SRPKs in cancer are underscored by the observed overexpression of SRPK1 in adult T-cell leukemia (Hishizawa et al, 2005) as well as in several types of solid tumors, such as colon, pancreatic, and breast carcinomas (Hayes et al, 2006; 2007; Plasencia et al, 2006). A more recent study demonstrated that SRPK1 is transcriptionally repressed by WT1, a well-known tumor suppressor, and overexpression of SRPK1 directly contributes to angiogenesis through induced VEGF alternative splicing that causes renal failure and Wilms’ tumors (Amin et al, 2011).…”

Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study

“…Intriguingly, withdrawal of immunosuppressive agents or donor lymphocyte infusion can induce remission in relapse of ATL after allogeneic HSCT, implying the presence of a graft-versus-ATL effect. [19][20][21][22][23] Because several antigens have recently been identified as putative targets for cytotoxic T-cell responses against ATL, 38,39 future development of cellular immunotherapy targeting these molecules would reduce the incidence of relapse and improve survival in patients with residual ATL after allogeneic transplantation. Further investigations are warranted to elucidate the association between the occurrence of GVHD and disease response among allografted patients with ATL because our preliminary analysis using a similar cohort 40 Finally, the use of unrelated cord blood was associated with lower survival, most likely a result of higher treatment-related mortality.…”