A functional receptor for B-cell-activating factor is expressed on human acute lymphoblastic leukemias.
B-lineage acute lymphoblastic leukemia (ALL) arises by transformation of a progenitor (pre-B) cell. Cure rates in adults remain low and treatment is complicated by support provided by the microenvironment to the leukemic cells, indicating an urgent need to better understand the factors that promote their survival. B-cell-activating factor (BAFF) and its receptor BAFF-R are important for survival and growth of mature normal and malignant B cells but are not expressed on pre-B cells. Unexpectedly, all cells in the primary Philadelphia chromosome (Ph)-positive and Ph-negative ALL samples tested were positive for high BAFF-R cell surface expression. BAFF-R was fully competent to bind BAFF, and stimulation of the receptor activated both the classic and the noncanonical NF-kappaB pathways. Recombinant BAFF supported survival of the ALL cells in the absence of stroma, and it significantly attenuated the rate of apoptosis caused by exposure to nilotinib, a drug used therapeutically to treat Ph-positive ALLs. Surprisingly, BAFF mRNA and protein were also expressed in the same cells but BAFF was not shed into the medium. Our report is the first showing universal expression of BAFF-R by pre-B ALL cells and opens the possibility of blocking its function as an adjuvant therapeutic strategy.
Parameswaran
Reshmi
R
Section of Molecular Carcinogenesis, Division of Hematology/Oncology, Childrens Hospital Los Angeles, CA 90027, USA.
Müschen
Markus
M
Kim
Yong-Mi
YM
Groffen
John
J
Heisterkamp
Nora
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053264:B-Cell Activating Factor / Q000378:metabolism / Q000494:pharmacology; D053265:B-Cell Activation Factor Receptor / Q000096:biosynthesis* / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D016688:Mice, Inbred NOD; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D012333:RNA, Messenger; D011994:Recombinant Proteins; C435926:TNFRSF13C protein, human
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