A CD40 Signalosome anchored in lipid rafts leads to constitutive activation of NF-kappaB and autonomous cell growth in B cell lymphomas.
B cell lineage non-Hodgkin's lymphomas (NHL-B) are neoplastic B cells that show dysregulated B lymphocyte growth characteristics. Unlike normal B cells, aggressive NHL-B cells show constitutive expression of nuclear NF-kappaB by maintaining an assembled, scaffold-like signaling platform, called a Signalosome within the lipid raft microdomain, extending from the cell membrane. The CD40 Signalosome appears to be initiated through autochthonous production and cognate binding of CD154 (CD40L, gp39) to CD40 by the lymphoma cell. Constitutive expression of NF-kappaB in NHL-B can be downregulated by treatment with antibodies to CD40 or CD154 that disrupt Signalosomes, inhibit lymphoma cell growth, and induce cell death. CD40 Signalosomes may provide a potentially vulnerable target for therapeutic intervention in NHL-B cells.
Pham
Lan V
LV
Department of Hematopathology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Tamayo
Archito T
AT
Yoshimura
Linda C
LC
Lo
Piao
P
Terry
Nicholas
N
Reid
Pamela S
PS
Ford
Richard J
RJ
D019013:CD40 Antigens / Q000032:analysis / Q000502:physiology*; D023201:CD40 Ligand / Q000032:analysis; D016923:Cell Death; D002455:Cell Division; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D021962:Membrane Microdomains / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D019013:CD40 Antigens; D016328:NF-kappa B; D023201:CD40 Ligand