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 Blood, 23 April 2009, Vol. 113, No. 17, pp. 4016-4026.
Prepublished online as a Blood First Edition Paper on January 8, 2009; DOI 10.1182/blood-2008-08-175901.

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Submitted August 26, 2008
Accepted December 11, 2008

Gene expression profiling of ATL patients: compilation of disease related genes and evidence for TCF-4 involvement in BIRC5 gene expression and cell viability

Cynthia A. Pise-Masison, Michael Radonovich, Kathleen Dohoney, John C. Morris, Deirdre O'Mahony, Min-Jung Lee, Jane Trepel, Thomas A. Waldmann, John E. Janik, and John N. Brady*

Laboratory of Cellular Oncology, CCR, NCI, NIH, Bethesda, MD, United States
Metabolism Branch, CCR, NCI, NIH, Bethesda, MD, United States
Medical Oncology Branch, CCR, NCI, NIH, Bethesda, MD, United States

* Corresponding author; email: bradyj{at}mail.nih.gov.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive and fatal disease. We have examined 32 patients with smoldering, chronic, lymphoma and acute leukemia using Affymetrix HG-U133A2.0 arrays. Using the BRB array program, we identified genes differentially expressed in leukemia cells compared to normal lymphocytes. Several unique genes were identified that were overexpressed in leukemic cells including TNFSF11, RGS13, MAFb, CSPG2, C/EBP{alpha} and TCF4. 200 of the most highly overexpressed ATL genes were analyzed by the PathwayStudioTM4.0 program. ATL leukemia cells were characterized by an increase in genes linked to "central" genes CDC2/cyclin B1, SYK/LYN, PCNA and BIRC5. Because of its potential therapeutic importance, we focused our studies on the regulation and function of BIRC5, whose expression was increased in 13 of 14 leukemia samples. TCF4 reporter assays and transfection of DN-TCF4 demonstrated that TCF4 regulates BIRC5 gene expression. Functionally, transfection of ATL cells with BIRC5 shRNA decreased BIRC5 expression and cell viability 80%. Clinical treatment of ATL patients with Zenapax® or bortezomib decreased BIRC5 expression and cell viability. These experiments represent the first direct experimental evidence that BIRC5 plays an important role in ATL cell viability and provides important insight into ATL genesis and potential targeted therapies.


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