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Blood, 1 August 2008, Vol. 112, No. 3, pp. 805-813.
Prepublished online as a Blood First Edition Paper on May 16, 2008; DOI 10.1182/blood-2007-11-126326.
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Submitted November 30, 2007
Accepted April 19, 2008
SALL4 is a key regulator of survival and apoptosis in human leukemic cells
Jainchang Yang, Li Chai, Chong Gao, Taylor C Fowles, Zaida Alipio, Hien Dang, Dan Xu, Louis M Fink, David C Ward, and Yupo Ma*
Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas, NV, United States
Joint Program in Transfusion Medicine, Brigham and Women's Hospital/Children's Hospital Boston, Boston, MA, United States
* Corresponding author; email: yma{at}nvcancer.org.
Increasing studies suggest that SALL4 may play vital roles in leukemogenesis and stem cell phenotypes. We have mapped the global gene targets of SALL4 using chromatin immunoprecipitation followed by microarray hybridization and identified over two-thousand, high-confidence, SALL4 binding genes in the human acute promyelocytic leukemic cell line, NB4. Analysis of SALL4 binding sites reveals that genes involved in cell death, cancer, DNA replication/repair, and cell cycle were highly enriched (p<0.05). These genes include 38 important apoptosis- inducing genes (TNF, TP53, PTEN, CARD9, CARD11, CYCS, LTA) and apoptosis-inhibiting genes (Bmi-1, BCL2, XIAP, DAD1, TEGT). Real-time PCR has shown that expression levels of these genes changed significantly after SALL4 knockdown, which ubiquitously led to cell apoptosis. Flow cytometry revealed that reduction of SALL4 expression in NB4 and other leukemia cell lines dramatically increased caspase-3, Annexin V, and DNA fragmentation activity. Bromodeoxyuridine-incorporation assays showed decreased numbers of S phase cells and increased numbers of G1- and G2- phase cells indicating reduced DNA synthesis, consistent with results from cell proliferation assays. In addition, NB4 cells that express low levels of SALL4 have significantly decreased tumorigenecity in immunodeficient mice. Our studies provide a foundation in the development of leukemia stem cell-specific therapy by targeting SALL4.
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