MYSM1-dependent checkpoints in B cell lineage differentiation and B cell-mediated immune response.

MYSM1 is a chromatin-binding histone deubiquitinase. mutations in humans result in lymphopenia whereas loss of in mice causes severe hematopoietic abnormalities, including an early arrest in B cell development. However, it remains unknown whether MYSM1 is required at later checkpoints in B cell development or for B cell-mediated immune responses. We analyzed conditional mouse models Tg.mb1-cre, Tg.CD19-cre, and Tg.CD21-cre with inactivation of at prepro-B, pre-B, and follicular B cell stages of development. We show that loss of at the prepro-B cell stage in Tg.mb1-cre mice results in impaired B cell differentiation, with an ∼2-fold reduction in B cell numbers in the lymphoid organs. Tg.mb1-cre B cells also showed increased expression of activation markers and impaired survival and proliferation. In contrast, was largely dispensable from the pre-B cell stage onward, with Tg.CD19-cre and Tg.CD21-cre mice showing no alterations in B cell numbers and largely normal responses to stimulation. MYSM1, therefore, has an essential role in B cell lineage specification but is dispensable at later stages of development. Importantly, MYSM1 activity at the prepro-B cell stage of development is important for the normal programming of B cell responses to stimulation once they complete their maturation process.