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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2308-2315.
Prepublished online as a Blood First Edition Paper on November 13, 2003; DOI 10.1182/blood-2003-06-1992.
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NEOPLASIA
IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells
Jun Won Lee,
Ho Yeon Chung,
Lori A. Ehrlich,
Diane F. Jelinek,
Natalie S. Callander,
G. David Roodman, and
Sun Jin Choi
From the Department of Medicine, Hematology/Oncology Division, University of Pittsburgh, Pittsburgh, PA; Department of Veterans Affairs Medical Center, Pittsburgh, PA; Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN; and the Department of Hematology/Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX.
Macrophage inflammatory protein–1 (MIP-1) gene expression is abnormally regulated in multiple myeloma (MM) owing to imbalanced expression of the acute myeloid leukemia–1A (AML-1A) and AML-1B transcription factors. We hypothesized that the increased expression ratios of AML-1A to AML-1B also induced abnormal expression of other hematopoietic and bone-specific genes that contribute to the poor prognosis of MM patients with high levels of MIP-1. We found that interleukin-3 (IL-3) was also induced by the imbalanced AML-1A and AML-1B expression in myeloma. IL-3 mRNA levels were increased in CD138+ purified myeloma cells with increased AML-1A–to–AML-1B expression from MM patients, and IL-3 protein levels were significantly increased in freshly isolated bone marrow plasma from MM patients (66.4 ± 12 versus 22.1 ± 8.2 pg/mL; P = .038). IL-3 in combination with MIP-1 or receptor activator of nuclear factor–kappa B ligand (RANKL) significantly enhanced human osteoclast (OCL) formation and bone resorption compared with MIP-1 or RANKL alone. IL-3 stimulated the growth of interleukin-6 (IL-6)–dependent and IL-6–independent myeloma cells in the absence of IL-6, even though IL-3 did not induce IL-6 expression by myeloma cells. These data suggest that increased IL-3 levels in the bone marrow microenvironment of MM patients with imbalanced AML-1A and AML-1B expression can increase bone destruction and tumor cell growth.
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