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A20 is a negative regulator of NF-κB, and mutational loss of A20 expression is involved in the pathogenesis of autoimmune diseases and B-cell lymphomas. To clarify the role of A20 in adult hematopoiesis, we generated conditional  A20  knockout mice ( A20 flox/flox  ) and crossed them with  Mx – 1Cre  ( MxCre   + ) and  ERT2Cre  ( ERT2Cre   + ) transgenic mice in which Cre is inducibly activated by endogenous interferon and exogenous tamoxifen, respectively.  A20 flox/flox  MxCre   +  ( A20Mx ) mice spontaneously exhibited myeloid proliferation, B cell apoptosis, and anemia with overproduction of pro-inflammatory cytokines. Bone marrow transplantation demonstrated that these changes were caused by hematopoietic cells. NF-κB was constitutively activated in  A20Mx  hematopoietic stem cells (HSCs), which caused enhanced cell cycle entry and impaired repopulating ability. Tamoxifen stimulation of  A20 flox/flox  ERT2Cre   +  ( A20ERT2 ) mice induced fulminant apoptosis and subsequent myeloproliferation, lymphocytopenia, and progressive anemia with excessive production of pro-inflammatory cytokines, as observed in  A20Mx  mice. These results demonstrate that A20 plays essential roles in the homeostasis of adult hematopoiesis by preventing apoptosis and inflammation. Our findings provide insights into the mechanism underlying A20 dysfunction and human diseases in which A20 expression is impaired.

Acquired Deficiency of A20 Results in Rapid Apoptosis, Systemic Inflammation, and Abnormal Hematopoietic Stem Cell Function