Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL.
Hodgkin lymphoma (HL) originates from the clonal expansion of malignant Hodgkin and Reed-Sternberg (HRS) cells. These B-cell-derived elements constitute less than 10% of the tumoral mass. The remaining tissue is comprised of an inflammatory infiltrate that includes myeloid cells. Myeloid cells activate B cells by producing BAFF and APRIL, which engage TACI, BCMA, and BAFF-R receptors on the B cells. Here, we studied the role of BAFF and APRIL in HL. Inflammatory and HRS cells from HL tumors expressed BAFF and APRIL. Unlike their putative germinal center B-cell precursors, HRS cells lacked BAFF-R, but expressed TACI and BCMA, a phenotype similar to that of plasmacytoid B cells. BAFF and APRIL enhanced HRS cell survival and proliferation by delivering nonredundant signals via TACI and BCMA receptors through both autocrine and paracrine pathways. These signals caused NF-kappaB activation; Bcl-2, Bcl-xL, and c-Myc up-regulation; and Bax down-regulation, and were amplified by APRIL-binding proteoglycans on HRS cells. Interruption of BAFF and APRIL signaling by TACI-Ig decoy receptor, which binds to and neutralizes BAFF and APRIL, or by small-interfering RNAs targeting BAFF, APRIL, TACI, and BCMA inhibited HRS cell accumulation in vitro and might attenuate HL expansion in vivo.
Chiu
April
A
Department of Pathology and Laboratory Medicine, Weill Medical College, Cornell University, 1300 York Ave, Rm C-410, New York, NY 10021, USA.
Xu
Weifeng
W
He
Bing
B
Dillon
Stacey R
SR
Gross
Jane A
JA
Sievers
Eric
E
Qiao
Xugang
X
Santini
Paul
P
Hyjek
Elizabeth
E
Lee
Joong-won
JW
Cesarman
Ethel
E
Chadburn
Amy
A
Knowles
Daniel M
DM
Cerutti
Andrea
A
D053264:B-Cell Activating Factor / Q000378:metabolism* / Q000494:pharmacology; D053301:B-Cell Maturation Antigen / Q000096:biosynthesis* / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020869:Gene Expression Profiling; D006689:Hodgkin Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction; D053303:Transmembrane Activator and CAML Interactor Protein / Q000096:biosynthesis* / Q000235:genetics; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism* / Q000494:pharmacology
D053264:B-Cell Activating Factor; D053301:B-Cell Maturation Antigen; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13