Restoration of T lymphopoiesis from myeloid progenitors by targeting of C/EBPα (LYM7P.721)

Loss of immune cell function with increased incidence of myeloid skewing and leukemia are well known features of the aging hematopoietic system. As one example, stem and progenitor cells (HSPCs) have greatly reduced potential to generate T lymphocytes. However, the underlying mechanisms are poorly understood. It was previously known that levels of the myeloid transcription factor C/EBPα rise with age and we asked if this might account for some of the previously described phenomena. C/EBPα deficient common myeloid progenitors (CMPs) had a distinct T cell gene expression signature that correlated with an increased potential for differentiation toward the T cell lineage. Moreover, the Notch signaling pathway activation was up-regulated in CMPs that were deficient in this transcription factor. To better understand the mechanisms underlying hematopoietic aging of T cell progenitors, we deleted C/EBPα in aged mice. Remarkably, that increased lymphoid differentiation of HSPCs in both culture and transplantation assays. These findings have implications for our understanding of the transcriptional wiring in lymphoid/myeloid progenitors. Additionally, the data support a model in which age-dependent alterations in gene expression affect lineage choice decisions and could sequentially cause immunosenescence and predispose the aged to myeloid leukemia.