AML-1A and AML-1B regulation of MIP-1α expression in multiple myeloma

Sun J. Choi, Tomoko Oba, Natalie S. Callander, Diane F. Jelinek, G. David Roodman

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Macrophage inflammatory protein-1α (MIP-1α) is produced in high concentration by multiple myeloma (MM) cells in about 70% of patients, and MIP-1α levels correlate with their disease activity. Patients who have high levels of MIP-1α have a poor prognosis. Furthermore, blocking MIP-1α expression in an in vivo model of human MM profoundly decreases both tumor burden and bone destruction, suggesting that MIP-1α is an important mediator of MM bone disease. Therefore, to analyze the regulation of MIP-1α production in MM, we cloned the human MIP-1α promoter and characterized the transcription factor (TF) motifs that control MIP-1α expression in MM cells. The proximal region of MIP-1α promoter was composed of 2 sets of identical transcription regulatory regions consisting of GATA-2+ AML-1+ C/EBPα 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-1α was examined. AML-1A mRNA was relatively overexpressed compared with AML-1B in MM cell lines that produced high levels of MIP-1α (> 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-1α. 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-1α. 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-1α production, while AML-1A did not further increase the already high levels of MIP-1α produced by these cells. Taken together, these data demonstrate that in patients with MM who produce increased concentrations of MIP-1α, 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.

Original languageEnglish (US)
Pages (from-to)3778-3783
Number of pages6
JournalBlood
Volume101
Issue number10
DOIs
StatePublished - May 15 2003
Externally publishedYes

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Macrophage Inflammatory Proteins
Multiple Myeloma
Acute Myeloid Leukemia
Messenger RNA
Bone
Cells
Cell Line
Nucleic Acid Regulatory Sequences
Bone Diseases

ASJC Scopus subject areas

  • Hematology

Cite this

AML-1A and AML-1B regulation of MIP-1α expression in multiple myeloma. / Choi, Sun J.; Oba, Tomoko; Callander, Natalie S.; Jelinek, Diane F.; Roodman, G. David.

In: Blood, Vol. 101, No. 10, 15.05.2003, p. 3778-3783.

Research output: Contribution to journalArticle

Choi, SJ, Oba, T, Callander, NS, Jelinek, DF & Roodman, GD 2003, 'AML-1A and AML-1B regulation of MIP-1α expression in multiple myeloma', Blood, vol. 101, no. 10, pp. 3778-3783. https://doi.org/10.1182/blood-2002-08-2641
Choi, Sun J. ; Oba, Tomoko ; Callander, Natalie S. ; Jelinek, Diane F. ; Roodman, G. David. / AML-1A and AML-1B regulation of MIP-1α expression in multiple myeloma. In: Blood. 2003 ; Vol. 101, No. 10. pp. 3778-3783.
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N2 - Macrophage inflammatory protein-1α (MIP-1α) is produced in high concentration by multiple myeloma (MM) cells in about 70% of patients, and MIP-1α levels correlate with their disease activity. Patients who have high levels of MIP-1α have a poor prognosis. Furthermore, blocking MIP-1α expression in an in vivo model of human MM profoundly decreases both tumor burden and bone destruction, suggesting that MIP-1α is an important mediator of MM bone disease. Therefore, to analyze the regulation of MIP-1α production in MM, we cloned the human MIP-1α promoter and characterized the transcription factor (TF) motifs that control MIP-1α expression in MM cells. The proximal region of MIP-1α promoter was composed of 2 sets of identical transcription regulatory regions consisting of GATA-2+ AML-1+ C/EBPα 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-1α was examined. AML-1A mRNA was relatively overexpressed compared with AML-1B in MM cell lines that produced high levels of MIP-1α (> 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-1α. 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-1α. 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-1α production, while AML-1A did not further increase the already high levels of MIP-1α produced by these cells. Taken together, these data demonstrate that in patients with MM who produce increased concentrations of MIP-1α, 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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