Beta-catenin signaling regulates acute adult T-cell leukemia/lymphoma

C254 The acute and lymphoma clinical subtypes of adult T-cell leukemia/lymphoma (ATLL) have a very poor prognosis, despite the fact that it has been known for decades that the etiologic agent of ATLL is the HTLV-1 virus, and that HTLV-1-encoded Tax plays a key role in HTLV-1-induced malignant transformation. Although Tax plays a critical role in the initial transformation process, Tax expression is frequently undetectable in the acute and lymphomatous forms of ATLL. Thus, targeting of Tax would not appear to present a viable strategy in the most advanced and rapidly progressive forms of ATLL. Recently it was demonstrated that Tax induces stabilization of beta-catenin and activation of nuclear beta-catenin signaling, and that, in a variety of hematologic malignancies, beta-catenin nuclear signaling promotes cell proliferation and survival. Here we demonstrate for the first time that (1) primary acute ATLL cells express beta-catenin, (2) beta-catenin expression occurs in the absence of Tax, (3) beta-catenin protein localizes to the cell nucleus in Tax-negative ATLL cells, and (4) transcriptional analysis of primary ATLL patient samples using Affymetrix arrays demonstrates high levels of expression of the beta-catenin transcriptional partner TCF4 and the beta-catenin/TCF4 target gene survivin. Recently survivin has been shown to be the most negative prognostic factor in ATLL. We have succeeded in transfecting primary ATLL cells, and have used this technique to transfect wild-type beta-catenin and a panel of constructs that block nuclear beta-catenin signaling (dominant-negative beta-catenin, dominant-negative TCF, E-cadherin and full-length beta-catenin antisense), as well as control siRNA and beta-catenin siRNA. These experiments demonstrated that in primary ATLL cells survivin and the potent antiapoptotic gene Bfl-1 are under the transcriptional control of beta-catenin. Analysis of the pathways leading to beta-catenin overexpression and activation in primary ATLL cells demonstrated a complex pattern of deregulatory events that stabilize beta-catenin and upregulate beta-catenin nuclear localization including Akt phosphorylation, CD45 silencing and activation of non-receptor tyrosine kinases. Recently it has been demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) such as celecoxib significantly down-regulate nuclear beta-catenin levels and block nuclear beta-catenin signaling. We screened a panel of NSAIDs against primary ATLL cells and HTLV-1-infected cell lines and found that celecoxib had the most-favorable ratio of potency to toxicity. Celecoxib treatment of primary ATLL cells inhibited beta-catenin nuclear localization, induced loss of survival gene expression, and induced cell death. Together these data identify nuclear beta-catenin as a novel therapeutic target in advanced, Tax-independent ATLL.