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Deregulation of c-Myc Confers Distinct Survival Requirements for Memory B Cells, Plasma Cells, and Their Progenitors¹

Sefat E. Khuda^*, William M. Loo^*, Siegfried Janz, Brian Van Ness and Loren D. Erickson^2,*

^* Department of Microbiology, University of Virginia, Charlottesville, VA 22908; Department of Pathology, University of Iowa, Iowa City, IA 52242; and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis MN 55455

Deregulation of the c-Myc oncogene is tightly associated with human and murine plasma cell (PC) neoplasms. Through the analysis of Ag-specific B cell responses in mice where Myc is targeted to the Igh C locus, we show here that c-Myc dramatically impairs the primary and secondary Ab response. This impairment is differentiation stage specific, since germinal center B cell formation, affinity maturation, and class switch recombination were intact. Examination of PC viability revealed that c-Myc triggered apoptosis only upon final maturation when Ab is secreted and is resistant to the survival factor BAFF (B cell-activating factor belonging to the TNF family). In contrast, PC precursors (PC_pre) that ultimately give rise to mature PCs survived normally and vigorously expanded with BAFF signaling. We further show that c-Myc also facilitates the apoptosis of memory B cells. Thus, C-Myc controls both cellular arms of long-lived B cell immunity than previously anticipated. Only when deregulation of c-Myc was combined with enforced Bcl-x_L expression were mature PCs able to survive in response to BAFF. These data indicate that the survival requirements for tumor-susceptible PC_pre and PCs are distinct and that tumor progression likely develops as PC_pre transition to functional PCs when apoptotic pathways such as members of the Bcl-2 family are disabled.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the American Cancer Society and the Leukemia Research Foundation (to L.D.E.) and by the University of Virginia Cancer Center for Core support.

² Address correspondence and reprint requests to Dr. Loren D. Erickson, Department of Microbiology, University of Virginia, Jordan Hall, Room 7034, 1300 Jefferson Park Avenue, Charlottesville, VA 22908. E-mail address: lde9w{at}virginia.edu

³ Abbreviations used in this paper: PC, plasma cell; TI, T cell independent; TD, T cell dependent; GC, germinal center; BM, bone marrow; MM, multiple myeloma; BAFF, B cell-activating factor belonging to the TNF family; BL, Burkitt’s lymphoma; BCMA, B cell maturation Ag; PC_pre, PC precursor; NP, (4-hydroxy-3-nitrophenyl)acetyl; KLH, keyhole limpet hemocyanin; ZVAD, benzylocarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone; DAPI, 4',6-diamidino-2-phenylindole; 7-AAD, 7-aminoactinomycin D; CT, cycle threshold; FO, follicular; CDK, cyclin-dependent kinase; MZ, marginal zone; AID, activation-induced cytidine deaminase; B_mem, B memory cell; TACI, transmembrane activator and calcium-modulator and cytophilin ligand interactor.