Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 4, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20201699
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Funding
- National Institutes of Health/National Institute of Allergy and Infectious Diseases [R01AI139117, R01AI119006]
- Starr Foundation consortium [I11-0027]
- National Institutes of Health [1DP2GM119419, DP1AI144248, 5U24AI118672]
- Robertson Foundation
- Damon Runyon Cancer Research Foundation Berger Foundation [DRG-2353-19]
- European Union's Horizon 2020 research and innovation program under Marie Sklodowska-Curie [765158]
- Damon Runyon Cancer Research Foundation [DRG-2274-16]
- Richard and Susan Smith Family Foundation
- Lymphoma Research Foundation
- Leukemia and Lymphoma Society Special Fellow Award
- American Society of Hematology Research Restart Award
- National Cancer Institute [R35CA220499]
- Ministerio de Ciencia, Innovacion y Universidades/Agencia Estatal de Investigacion Ramon y Cajal Awardee [RYC2013-13546]
- Searle Scholars Program
- Beckman Young Investigator Program
- Sloan Fellowship in Chemistry
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During affinity maturation, GC B cells undergo proliferation and hypermutation in the dark zone, followed by selection in the light zone. Cyclin D3 plays a crucial role in controlling the anatomical segregation and cell cycle of GC B cells, and a specific mutation can lead to clonal B cell lymphoproliferation.
During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by inertia. We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma?associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.
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