APRIL promotes cell-cycle progression in primary multiple myeloma cells: influence of D-type cyclin group and translocation status.
A proliferation-inducing ligand (APRIL) promotes survival and drug resistance in multiple myeloma (MM) cell lines. We studied the effect of APRIL on cell-cycle behavior in primary MM cells and correlated our findings with D-type cyclin expression by immunohistochemistry and/or Western blotting. In MM cases, expressing cyclin D2 APRIL significantly increased the percentage of CD138(+) cells in S + G(2)/M phase (from 8.4% ± 1.9% to 14.3% ± 2.6%, n = 15, P < .01), whereas a lesser effect was seen in cases expressing cyclin D1 (n = 18). Cell-cycle response to APRIL was most marked for cyclin D2-expressing cases with IgH translocations (P < .01) and was accompanied by increased expression of cyclin D2, CDK4, CDK6, and phospho-retinoblastoma protein. Cell-cycle proteins in cyclin D1(+) cells were not modulated by APRIL. Surface expression of B-cell maturation antigen and transmembrane activator and calcium-modulating cyclophilin ligand interactor was not significantly different between cyclin D1(+) and D2(+) MM cells. We observed activation of nuclear factor-κB and PI3-kinase pathways in response to APRIL in both cyclin D1(+) and D2(+) MM cells. In conclusion, APRIL stimulates G(1)/S progression in cyclin D2(+) MM cells bearing IgH translocations but has minimal effect on cyclin D1(+) cells, suggesting MM cells from different cyclin D/translocation classes rely on different mechanisms for cell-cycle re-entry.
Quinn
John
J
Department of Haematology, University College London Cancer Institute, London, UK.
Glassford
Janet
J
Percy
Laura
L
Munson
Philippa
P
Marafioti
Teresa
T
Rodriguez-Justo
Manuel
M
Yong
Kwee
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D056741:Cyclin D / Q000378:metabolism*; D056742:Cyclin D2 / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D053668:Syndecan-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism / Q000494:pharmacology*
D018797:Cell Cycle Proteins; D003470:Culture Media; D056741:Cyclin D; D056742:Cyclin D2; C508241:SDC1 protein, human; D053668:Syndecan-1; C114631:TNFSF13 protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13