IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells.
Macrophage inflammatory protein-1 alpha (MIP-1 alpha) 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 alpha. 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 alpha or receptor activator of nuclear factor-kappa B ligand (RANKL) significantly enhanced human osteoclast (OCL) formation and bone resorption compared with MIP-1 alpha 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.
Lee
Jun Won
JW
Department of Medicine, Hematology/Oncology Division, University of Pittsburgh, and Department of Vetrerans Affairs Medical Center, PA 15213, USA.
Chung
Ho Yeon
HY
Ehrlich
Lori A
LA
Jelinek
Diane F
DF
Callander
Natalie S
NS
Roodman
G David
GD
Choi
Sun Jin
SJ
D000906:Antibodies / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000502:physiology; D001862:Bone Resorption / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D054407:Chemokine CCL4; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics* / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000473:pathology* / Q000503:physiopathology*; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand; D012333:RNA, Messenger / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000906:Antibodies; D002352:Carrier Proteins; D054407:Chemokine CCL4; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D007377:Interleukin-3; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D053245:RANK Ligand; D012333:RNA, Messenger; C493728:RUNX1 protein, human; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D014157:Transcription Factors