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Prepublished online as a Blood First Edition Paper on January 30, 2003; DOI 10.1182/blood-2002-08-2641.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 3778-3783
CHEMOKINES
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
From the Department of Medicine
Hematology/Oncology, University of Pittsburgh, PA; the Department of
Medicine/Hematology, University of Texas Health Science Center, San
Antonio; the Department of Immunology, Mayo Clinic, Rochester, MN; and
the VA Medical Center, Pittsburgh, PA.
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
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 2 sets of
identical transcription regulatory regions consisting of
GATA-2+ AML-1+ C/EBP motifs. Since 2 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 overexpressed compared with AML-1B in MM cell lines that
produced high levels of MIP-1 (> 1 ng/mL per 106 cells
per 72 hours), but AML-1A was not increased in MM cell lines that
expressed less than 200 pg/mL MIP-1. More importantly, the ratio of
AML-1A to AML-1B mRNA levels was also increased in 3 of 3 highly
purified myeloma cells from patients with MM who expressed increased
amounts of MIP-1. The ratio of AML-1A to AML-1B mRNA in patients
with MM was 8-fold higher than in healthy controls.
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 patients with MM who
produce increased concentrations of MIP-1, the relative level of
AML-1B is significantly decreased compared with healthy
controls. 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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