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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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NEOPLASIA

SALL4 is a key regulator of survival and apoptosis in human leukemic cells

Jianchang Yang1, Li Chai2, Chong Gao2, Taylor C. Fowles1, Zaida Alipio1, Hien Dang1, Dan Xu1, Louis M. Fink1, David C. Ward1, and Yupo Ma1

1 Division of Laboratory Medicine, Nevada Cancer Institute, Las Vegas; and 2 Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital/Children's Hospital Boston, Harvard Medical School, Boston, MA

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 more than 2000 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 < .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 polymerase chain reaction 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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J. D. Bard, P. Gelebart, H. M. Amin, L. C. Young, Y. Ma, and R. Lai
Signal transducer and activator of transcription 3 is a transcriptional factor regulating the gene expression of SALL4
FASEB J, May 1, 2009; 23(5): 1405 - 1414.
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