Cartography of emergency myelopoiesis identifies conserved molecular activation modules

Hematopoietic stem and progenitor cells (HSPC) respond to infections, inflammation, and regenerative challenges using cellular and molecular mechanisms termed emergency myelopoiesis (EM) pathways. However, it remains unclear whether all parts of the hematopoietic hierarchy are similarly activated by different EM inducers. Here, we generate a generalizable and comprehensive cell annotation method together with a refined quantitative model of hematopoietic differentiation using single cell RNA sequencing (scRNA-seq) of HSPCs, which we apply to a broad range of EM contexts. We uncover multiple strategies to enhance myelopoiesis acting at different levels of the HSPC hierarchy, which are also associated with both unique and shared transcriptional response modules. In particular, we identify a myeloid progenitor-based signature associated with EM pathway engagement across multiple inflammatory challenges, which predicts outcome in both pediatric and adult human acute myeloid leukemia. Collectively, our work illuminates fundamental regulatory mechanisms in hematopoietic regeneration and identifies a common EM signature that informs outcome in disease contexts.