APOBEC2 deficiency disrupts hematopoietic lineage commitment, resulting in emergence of dual identity lymphocytes in mice and humans

Abstract

APOBEC2 is a well-conserved member of the AID/APOBEC family of cytidine deaminases. Most members of the family catalyze the conversion of cytosine to uracil either in DNA or RNA, thereby acting as DNA mutators and/or RNA editors. APOBEC2 is the only family member that appears to be catalytically inactive. Instead, its ability to bind, but not deaminate DNA, has been co-opted into a transcription-factor-like functionality. APOBEC2 is highly expressed in skeletal muscle, where it functions to promote and maintain muscle identity by suppressing nonmuscle genes. APOBEC2 is also expressed in several cell types within the hematopoietic lineage. Here, we show that loss of APOBEC2 disrupts proper lymphoid lineage differentiation, resulting in the emergence of lymphoid cells expressing both TCRs and BCRs, as well as additional markers that define a mixed T and B cell identity in both mice with a depletion in Apobec2 gene and humans with mutations in it. We further show that these T/B cells present dual functionality. Finally, we elucidate the molecular mechanisms associated with APOBEC2 deficiency that led to disruption of cell fate determination. Overall, our results establish APOBEC2 as a terminal repressor of B cell fates within the T cell lineage, whose loss results in disease outcomes in mice and humans.