is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells.

Recent studies have reported that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of occur in myeloid malignancies, and hematopoietic-specific loss of induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of loss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show that loss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression of and , myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing of in human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast to loss, loss does not contribute to enhanced HSC self-renewal or cooperate with to induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role of as a key epigenetic regulator. These results indicate that and share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation.