Deregulation of c-Myc Confers distinct survival requirements for memory B cells, plasma cells, and their progenitors. J Immunol 2008 Dec 01;181(11):7537-49
Date
11/20/2008Pubmed ID
19017943Pubmed Central ID
PMC2841033DOI
10.4049/jimmunol.181.11.7537Abstract
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 Calpha 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, Calpha-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.
Author List
Khuda SE, Loo WM, Janz S, Van Ness B, Erickson LDAuthor
Siegfried Janz MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntibody Formation
Apoptosis
B-Cell Activating Factor
Cell Survival
Gene Targeting
Germinal Center
Humans
Immunologic Memory
Mice
Mice, Transgenic
Neoplastic Stem Cells
Plasma Cells
Plasmacytoma
Precursor Cells, B-Lymphoid
Proto-Oncogene Proteins c-myc
Quantitative Trait Loci
Somatic Hypermutation, Immunoglobulin
bcl-X Protein
