Targeting antiapoptotic A1/Bfl-1 by in vivo RNAi reveals multiple roles in leukocyte development in mice
- Author(s)
- Ottina, E; Grespi, F; Tischner, D; Soratroi, C; Geley, S; Ploner, A; Reichardt, HM; Villunger, A; Herold, MJ;
- Details
- Publication Year 2012-06-21,Volume 119,Issue #25,Page 6032-6042
- Journal Title
- BLOOD
- Publication Type
- Journal Article
- Abstract
- Gene-targeting studies in mice have identified the essential roles of most prosurvival Bcl-2 family members in normal physiology and under conditions of stress. The function of one member, Bcl2a1/Bfl-1/A1, is only poorly understood because of quadruplication of its gene locus in mice, hindering conventional knockout studies. To overcome this problem, we generated mouse models allowing traceable constitutive or reversible ablation of A1 in the hematopoietic system by RNA interference. Knockdown of A1 impaired early stages of T-cell differentiation, B-cell homeostasis, and sensitized transitional as well as follicular B cells to apoptosis induced by ligation of the B-cell receptor. As a consequence, B-cell proliferation in response to mitogens was severely impaired, whereas that of T cells appeared unaffected. Furthermore, depending on the extent of A1 knockdown, granulocytes showed increased spontaneous death in culture or failed to accumulate in significant numbers in vivo. These models highlight the critical role of A1 in leukocyte development and homeostasis, constituting valuable tools for investigating presumed roles of this Bcl-2 family member in immunity, tumorigenesis, and drug resistance. (Blood. 2012; 119(25): 6032-6042)
- Publisher
- AMER SOC HEMATOLOGY
- Keywords
- CHRONIC LYMPHOCYTIC-LEUKEMIA; BCL-2 HOMOLOG A1; B-CELLS; HEMATOPOIETIC COMPARTMENT; INDUCED APOPTOSIS; T-LYMPHOCYTES; UP-REGULATION; EXPRESSION; SURVIVAL; GENE
- Research Division(s)
- Molecular Genetics Of Cancer
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418769/
- Publisher's Version
- https://doi.org/10.1182/blood-2011-12-399089
- Terms of Use/Rights Notice
- Copyright © 2013 by American Society of Hematolog
Creation Date: 2012-06-21 12:00:00