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Prepublished online as a Blood First Edition Paper on January 30, 2003; DOI 10.1182/blood-2002-08-2641.
Submitted August 29, 2002
Accepted November 25, 2002
AML-1A and AML-1B regulation of MIP-1 expression in multiple myeloma
Sun J Choi, Tomoko Oba, Natalie S Callander, Diane F Jelinek, and G David Roodman*
Department of Medicine-Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA
Department of Medicine/Hematology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
Department of Immunology, Mayo Clinic, Rochester, MN, USA
* Corresponding author; email: roodmangd{at}msx.upmc.edu.
Macrophage inflammatory protein-1 (MIP-1) is produced in high concentration by multiple myeloma (MM) cells in about 70% of patients, and MIP-1 levels correlate with their disease activity. Patients who have high levels of MIP-1 have a poor prognosis. Furthermore, blocking MIP-1 expression in an in vivo model of human multiple myeloma (MM) profoundly decreases both tumor burden and bone destruction, suggesting that MIP-1 is an important mediator of MM bone disease. Therefore, to analyze the regulation of MIP-1 production in MM, we cloned the human MIP-1 promoter and characterized the transcription factor (TF) motifs that control MIP-1 expression in MM cells. The proximal region of MIP-1 promoter was composed of two sets of identical transcription regulatory regions consisting of GATA-2 + AML-1 + C/EBP motifs. Since two alternatively spliced variants of the acute myeloid leukemia-1 (AML-1) class of TFs can bind the AML-1 region, AML-1A and AML-1B, the relationship between the expression levels of AML-1A or AML-1B in MM cells and their capacity to express MIP-1, was examined. AML-1A mRNA was relatively over-expressed compared to AML-1B in MM cell lines that produced high levels of MIP-1 (>1ng/ml / 106 cells / 72hrs), but AML-1A was not increased in MM cell lines that expressed less than 200pg/ml of MIP-1. More importantly,the ratio AML-1A to AML-1B mRNA levels were also increased in 3 of 3 highly purified myeloma cells from MM patients that expressed increased amounts of MIP-1. The ratio of AML-1A to AML-1B mRNA in MM patients was 8-fold higher than in normals. Transduction of AML-1B into the MM derived MM.1S and ARH-77 cells totally blocked MIP-1 production, while AML-1A did not further increase the already high levels of MIP-1 produced by these cells. Taken together, these data demonstrate that in MM patients that produce increased concentrations of MIP-1, the relative level of AML-1B is significantly decreased compared to normals. The data suggest that strategies that enhance AML-1B expression or decrease AML-1A in MM cells may be beneficial therapeutically.
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