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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

11/20/2008

Pubmed ID

19017943

Pubmed Central ID

PMC2841033

DOI

10.4049/jimmunol.181.11.7537

Abstract

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 LD

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antibody 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
jenkins-FCD Prod-411 e00897e83867fcfa48419861683711f8d99adb75