Plasmodium Infection Promotes Genomic Instability and AID-Dependent B Cell Lymphoma.
Chronic infection with Plasmodium falciparum was epidemiologically associated with endemic Burkitt's lymphoma, a mature B cell cancer characterized by chromosome translocation between the c-myc oncogene and Igh, over 50 years ago. Whether infection promotes B cell lymphoma, and if so by which mechanism, remains unknown. To investigate the relationship between parasitic disease and lymphomagenesis, we used Plasmodium chabaudi (Pc) to produce chronic malaria infection in mice. Pc induces prolonged expansion of germinal centers (GCs), unique compartments in which B cells undergo rapid clonal expansion and express activation-induced cytidine deaminase (AID), a DNA mutator. GC B cells elicited during Pc infection suffer widespread DNA damage, leading to chromosome translocations. Although infection does not change the overall rate, it modifies lymphomagenesis to favor mature B cell lymphomas that are AID dependent and show chromosome translocations. Thus, malaria infection favors mature B cell cancers by eliciting protracted AID expression in GC B cells. PAPERCLIP.
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA. Electronic address: drobbiani@rockefeller.edu.
Davide F
DF
Robbiani
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Stephanie
S
Deroubaix
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Niklas
N
Feldhahn
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Thiago Y
TY
Oliveira
Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Elsa
E
Callen
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Qiao
Q
Wang
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Mila
M
Jankovic
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Israel T
IT
Silva
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Philipp C
PC
Rommel
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
David
D
Bosque
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Tom
T
Eisenreich
Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
André
A
Nussenzweig
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA. Electronic address: nussen@rockefeller.edu.
Michel C
MC
Nussenzweig
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D002908:Chronic Disease; D003564:Cytidine Deaminase / Q000378:metabolism; D004261:DNA Replication; D016158:Genes, p53; D042822:Genomic Instability; D018858:Germinal Center / Q000469:parasitology; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008288:Malaria / Q000150:complications* / Q000235:genetics* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D016788:Plasmodium chabaudi / Q000502:physiology*; D014178:Translocation, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase